The World Health Organization (WHO) estimated that in June 2005 6.5 million people living in resource-limited settings were in urgent need of antiretroviral treatment (ART) . Despite formidable logistical hurdles, access to treatment in such settings is expanding, but one of the major challenges facing ART programmes is the overlapping tuberculosis (TB) epidemic, particularly in the countries of southern Africa . Rates of HIV-associated TB have reached unprecedented levels in some communities . Prior to availability of ART, annual TB incidence rates were reported to exceed 50% among Africans with WHO stage 3 and 4 disease attending a hospital-based HIV clinic in Cape Town, South Africa . Consequently, TB constitutes a major cause of morbidity and mortality among patients accessing ART services in these settings. This complicates clinical management [5–7] and may potentially compromise ART outcomes.
A recent study reported the incidence and risk factors for TB among patients receiving ART in a hospital-based outpatient cohort in Cape Town . Although ART resulted in a major reduction in risk of TB , a substantial incidence nevertheless persisted after 5 years of treatment . This ongoing burden of TB has important implications for TB control [10,11]. If life expectancy is greatly extended by ART and yet the annual risk of TB remains chronically heightened, then ART may not favourably impact lifetime risk of TB. In such a scenario, the potential impact of ART on TB control at the community level is greatly undermined .
The present study builds on our previous findings within a hospital-based outpatient cohort  by examining the burden of TB within a community-based ART programme in an urban township. Both the burden and the impact of TB on treatment outcomes within such programmes remain unknown. Moreover, identification of effective strategies to reduce the burden of TB during ART depends upon the accurate identification of risk factors for this disease, and findings from the two existing studies from sub-Saharan Africa disagree on this point [8,12]. Therefore, the present study determined the prevalence and incidence of TB and associated risk factors within a large community-based ART service in Cape Town and also addressed the hypothesis that TB undermines ART outcomes.
Antiretroviral treatment programme
The ART service based at the Gugulethu Community Health Centre in Cape Town has previously been described in detail [13–15]. The district has a predominantly African population of over 300 000, the vast majority of whom live in conditions of low socioeconomic status. In 2003, the antenatal HIV seroprevalence was 28% and the annual TB notification rate exceeded 1000/100 000 . National guidelines for the use of ART were based on the WHO 2002 recommendations , which advise treatment for those with a prior AIDS diagnosis (WHO stage 4 disease) or a blood CD4 cell count < 200 cells/μl. First-line ART comprised stavudine and lamivudine plus a non-nucleoside reverse transcriptase inhibitor in standard doses (predominantly efavirenz or nevirapine). The second-line regimen for those failing the first-line treatment comprised lopinavir/ritonavir, zidovudine and didanosine. All treatment was free of charge. Treatment adherence and viral load suppression < 400 copies/ml in this cohort both exceeded 90% at 1 year [14,18]. All patients with CD4 cell counts < 200 cells/μl received prophylaxis with daily cotrimoxazole or dapsone. No patients received isoniazid prophylaxis. In addition to scheduled clinic appointments at 4, 8 and 16 weeks and every 16 weeks thereafter, patients had open access to the clinic for medical problems. Deaths and losses to follow-up were ascertained by active community-based follow-up as described previously .
Patients were referred to the ART programme from 10 primary HIV clinics in the district or from antenatal and TB clinics. Details of previous episodes of TB or treatment for current TB were obtained from documentation from the referring clinicians and details were cross-checked with patients. The time between enrollment of a patient in the service and initiation of ART was approximately 1 month, permitting thorough evaluation of patients for possible active TB and other comorbidity as well as preparation for ART. Available investigations for TB included sputum microscopy and culture, chest radiology, abdominal ultrasonography, and fine-needle aspiration of lymphadenopathy for cytology. Nebulized sputum induction was available when necessary. Patients requiring inpatient care were referred to a nearby 200-bed secondary hospital.
Prevalent TB was defined as (a) TB diagnoses made prior to programme entry for which antituberculosis treatment was still being received at enrollment; (b) new TB diagnoses established in the interval between enrollment and initiation of ART; or (c) TB diagnoses confirmed during early ART but for which the symptoms were present prior to initiation of ART. Incident TB comprised TB cases for which the date of symptom onset and date of diagnosis were both after ART initiation. ‘Pulmonary sputum-positive’ TB was diagnosed on the basis at least one positive sputum culture of Mycobacterium tuberculosis or two sputum smears containing acid-fast bacilli in the context of a compatible clinical illness. ‘Pulmonary sputum-negative’ TB was based upon negative smears and cultures for M. tuberculosis in the context of clinically and radiologically compatible illness of at least 3 week's duration that did not respond to administration of simple antibiotics but responded to subsequent antituberculosis treatment. Diagnosis of extrapulmonary TB was based upon a combination of clinical, radiological and histopathological findings and response to antituberculosis treatment.
Structured clinical records were maintained on all patients screened on entry to the ART programme and this information was transferred on a weekly basis to a computer database. Where necessary, results of sputum tests were cross-checked with the central TB laboratory electronic records. Data were analysed from the start of the programme in September 2002 until data censorship in August 2005. Patients were considered for analysis if they enrolled into the programme by April 2005 so they would have at least 4 months of follow-up on ART. Collection of data on this study population for research purposes was approved by the Research Ethics Committee of the University of Cape Town and all patients enrolled gave written informed consent.
Data were analysed using STATA version 9.0 (College Station, Texas, USA). Wilcoxon rank-sum and Fisher's exact tests were used to compare medians and proportions, respectively. Trends in medians were analysed using Cuzick's non-parametric trend test . TB incidence rates were calculated from ART initiation, with person-time censored at the end of August 2005 for individuals without TB who were alive and retained by the service. Person-time accrued during antituberculosis treatment was excluded from the denominator when calculating TB incidence rates. Rates, rate ratios and 95% confidence intervals (CI) were calculated using methods described by Breslow and Day , and product-limit methods were used to estimate the probability of TB-free survival through time. All statistical tests were two-sided at α = 0.05.
In multivariate analysis, logistic regression was used to estimate the odds ratios of prevalent TB at entry into the programme according to participant demographic characteristics, clinical measures and CD4 cell count and viral load measured at baseline. Separate Poisson regression models were used to estimate the relative incidence of TB during follow-up, with each follow-up interval considered separately for participants. For this, generalized estimating equations with the Huber–White sandwich estimator were used to account for the intraindividual correlation of CD4 cell count and viral load measurements of participants followed through time . Results are presented as incidence rate ratios and 95% CI. In addition, Cox's proportional hazards models were constructed to analyse the association between prevalent and incident TB and mortality in the programme. For all multivariate models, independent variables were included if they demonstrated an appreciable association with the outcome of interest, or if their removal affected the associations involving other covariates.
Patient characteristics and follow-up
Between September 2002 and April 2005, 1002 patients were enrolled into the programme. Those aged < 15 years (n = 37) and those with prior ART exposure (n = 19) or missing data files (n = 2) were excluded. Among the 944 patients remaining in the analysis, the median age was 32 years [interquartile range (IQR), 28–38] and 73% were female. Disease was classified as WHO disease stage 3 and 4 among 51% and 28% of patients, respectively. The median baseline CD4 cell count was 96 cells/μl (IQR, 46–156) and plasma viral load exceeded 5.0 log10 copies/ml in 42% of patients. ART was subsequently received by 756 (80%) of enrolled patients. The median interval between programme enrollment and initiation of ART was 35 days (IQR, 28–57). The median duration of follow-up on ART was 311 days (IQR, 160–517), with a total of 782 person-years of observation accrued. There were 58 (8%) deaths; 17 (2%) patients were lost to follow up; and 25 (4%) were transferred-out or moved out of area.
Previous history of tuberculosis
A previous history of TB was recorded among 477 (52%) of 923 patients for whom the information was available; of these, 80 (17%) patients had a history of two or more episodes of TB. The percentages of previous TB episodes that occurred within 1, 2 and 3 years of enrollment into the programme were 32%, 70% and 90%, respectively. A previous history of TB was recorded among 58% and 66% of patients with stage 3 disease and stage 4 disease, respectively. TB was pulmonary in 78% of cases and the remainder was extrapulmonary.
Among patients entering the programme, 238 (25%) had prevalent TB and overall 67% of enrolled patients had a history of either previous or prevalent TB. Those that had prevalent TB included 140 (15%) who were receiving antituberculosis treatment and had done so for a median of 3 months (IQR, 2–5) prior to enrollment in the ART programme; 74 (8%) who were confirmed to have new diagnoses of active TB prior to initiating ART; and 24 (3%) whose diagnoses of TB were confirmed after initiating ART but whose symptom onset preceded ART commencement. Among those with prevalent TB, 73% was pulmonary and 27% extrapulmonary. In a multivariate model, prevalent TB was independently associated with advanced WHO stage of disease, low baseline CD4 cell count and high plasma viral load (Table 1). Risk of prevalent TB was lower among those who had a previous history of TB; the more recent the episode of TB, the greater the degree of protection (Ptrend = 0.007).
Incident tuberculosis while taking antiretroviral therapy
TB was diagnosed among 81 (10.7%) patients following initiation of ART. By the end of the first year of ART, the cumulative percentage of patients having either previous or currently active TB was 70%. Of the 81 cases of incident TB, the percentages of pulmonary and extrapulmonary disease (78% and 22%, respectively) were similar to those in prevalent TB. Among the 64 patients with pulmonary TB (58) or radiographically evident miliary TB (six), sputum samples were obtained from 56 and disease was sputum smear positive in 41% but culture positive in 81%.
Rates of TB were highest in the first 3 months of ART and decreased during ongoing treatment (Table 2). The incidence in the first year of ART was 13.4/100 person-years (95% CI, 10.4–16.9) but was threefold lower during the second and third years of treatment (4.5/100 person-years; 95% CI, 1.59–5.55) (P < 0.001). Multivariate analysis revealed that current CD4 cell count (measured in the preceding 4-month interval) was the only variable significantly associated with risk of incident TB during treatment (Table 3): during ART, an increase of 100 cells/μl was associated with a 25% lower risk of TB (P = 0.007).
Impact of tuberculosis on immunological and virological responses to antiretroviral therapy
Viral load and CD4 cell count responses to ART were determined for patients who had new diagnoses of TB within the programme prior to ART initiation and for those who developed incident TB during the first 4 months of treatment (n = 120). These were compared with the responses observed among those who remained free of TB (n = 615). The CD4 cell count and viral load outcomes in these two groups did not significantly differ (Table 4), indicating that treatment responses among survivors were not affected by prevalent or incident TB or its treatment.
The number of patients that could be evaluated at each time point decreased with time (Table 4), largely because patients enrolled in the later months of the recruitment period would not have completed 48 weeks of follow-up at the time of data censorship. However, the same finding was also observed when analysis was restricted to the subset of patients with 48-week outcomes.
Impact of prevalent and incident tuberculosis on mortality
The survival of patients who did or who did not have prevalent TB diagnosed at enrollment to the ART programme is shown in Fig. 1a and the survival patients who did or did not develop incident TB during ART is shown in Fig. 1b. These plots show that, following initiation of ART, both prevalent and incident TB were associated with a probability of death of approximately 15–20% at 1 year compared with 7–8% among those who were free of TB.
This study has documented a huge burden of TB among patients accessing a community-based ART service in South Africa. This service formed part of the national ART roll-out programme and so the findings are likely to be more applicable to other ART roll-out programmes in resource-limited settings than previously published data. Immunodeficiency was typically very advanced at programme entry and was associated with an extremely high prevalence of TB. By the end of the first year of ART, the cumulative proportion of patients who had one or more current or previous episodes of TB was 70%. Moreover, although ART was associated with substantial reductions in TB incidence, which were dependent upon CD4 cell count, a high TB incidence rate nevertheless persisted after 3 years.
The vast majority of episodes of previous TB occurred among patients in the 2–3 years preceding programme enrollment and were, therefore, likely to have been attributable to HIV infection. The large proportion of patients with previous TB did not simply reflect their referral source since only a small proportion were referred directly from TB clinics; the remainder came from pre-ART HIV and antenatal clinics. Many of these TB episodes may have represented missed opportunities for earlier entry to the ART programme. The very high prevalence of TB was strongly associated with advanced immunodeficiency and undoubtedly reflected late entry of patients to the ART programme. Reasons underlying late access such as barriers to healthcare access, health system delays, or inappropriately restrictive ART treatment criteria need to be carefully explored and addressed [22,23].
It has been suggested that HIV-infected patients with previous TB should receive secondary prophylaxis with isoniazid . However, our data show that a previous history of TB was partially protective against prevalent TB: the more recent the episode the greater the protection. This may reflect a time-dependent reduction in TB risk owing to sterilization of active and latent TB. Routine use of isoniazid prophylaxis among HIV-infected patients irrespective of previous history of TB should be implemented prior to ART in settings of high TB incidence to reduce the burden of TB upstream of the ART programme.
The TB incidence rate in the first 3 months of ART was extremely high, despite active screening for TB prior to ART initiation. This early burden of disease may represent progression of subclinical disease that remained undetected in the pre-ART screening period and rapid progression of either newly reactivated disease or exogenous infection. Immune reconstitution disease may have been responsible for some of these cases , although the available data did not permit this distinction to be made. Sputum culture was a far more sensitive diagnostic test for incident TB than sputum smear alone (81% versus 41%) and should be used where available. Diagnoses may be missed or considerably delayed in many resource-limited settings where facilities for mycobacterial culture are generally not available.
The TB incidence rate decreased during 2–3 years of ART to approximately 4.5/100 person-years, which is still extremely high. The long-term rate we reported in the Cape Town AIDS Cohort (CTAC) was lower (1.0/100 person-years) ; this may reflect the fact that patients in the present study were generally of lower socioeconomic status, lived in a community with a very high TB incidence and had a median baseline CD4 cell count that was much lower than that of patients within CTAC (96 versus 242 cells/μl). Moreover, in the present study, we report all TB diagnoses rather than just those with microbiological confirmation. The key findings of the present study are likely to be more generalisable to other settings, although the absolute burden of TB in ART programmes may differ according to the TB incidence rates in the local community . The high ongoing rate of TB was observed in the present cohort despite excellent virological and immunological outcomes ; rates may be higher in programmes with poorer ART outcomes.
We found that CD4 cell count measured in the preceding 4-month interval (current CD4 cell count) was the dominant risk factor for incident TB. The association was strong, with a 100 cell/μl rise in CD4 cell count being associated with a 25% lower risk of TB (P = 0.007). Therefore, establishment and maintenance of virological suppression to maximize CD4 cell recovery is a critical objective to reduce risk of TB during ART. Late initiation of ART increases the time period during which the patients are most vulnerable to morbidity and mortality  and also limits long-term functional and cell number immune recovery [25–27]. Late initiation of ART is likely to be a key factor associated with the ongoing high TB incidence during our ART programme. Other factors potentially contributing to this burden of TB also need investigation, including nosocomial transmission of TB within ART clinics. No policies exist within the national ART programme guidelines to address the possibility of nosocomial TB transmission and this issue needs to be urgently addressed.
In a similar township in the Cape Town area with comparable HIV prevalence and TB incidence, the TB incidence rate among non-HIV-infected people was approximately 0.6/100 person-years in 2004 . Using this as an estimate, we can conclude that in the present study TB rates after 2–3 years of ART were still 5- to 10-fold higher than rates among non-HIV-infected people. The very high burden of TB occurring before ART initiation, together with the ongoing high incidence during ART, has important implications for TB control. Major increases in life expectancy in the context of such a high ongoing risk of TB are likely to result in a high lifetime risk of TB. This will greatly undermine the potential for ART to contribute to TB control, especially in settings like this where HIV prevalence among adults is approximately 30%. Earlier initiation of ART, however, may reduce both the burden of TB before ART initiation and the longer-term TB incidence. Additional benefit may also be derived from concurrent administration of isoniazid prophylaxis during ART, and studies to examine this are needed. However, our finding that the sensitivity of sputum smear microscopy is greatly inferior to sputum culture complicates potential implementation of such treatment, as prior exclusion of active TB is an important prerequisite to the initiation of isoniazid prophylaxis.
We hypothesized that the overlap of antituberculosis treatment with ART would compromise treatment outcomes owing to increased pill burden, pharmacokinetic drug interactions and drug cotoxicities. Patients in the Cape Town AIDS Cohort who developed incident TB were shown to have poor long-term immunological recovery during 144 weeks of ART compared with those who remained free of TB . However, that analysis encompassed immunological recovery both preceding TB diagnosis and after diagnosis and so might be entirely explained by the fact that TB would have been more likely to develop among poor immunological responders. In the present study, however, the design of the analysis specifically examined the impact of TB and TB treatment on subsequent immunovirological outcomes. We demonstrated that TB present at baseline or developing during the first 4 months of ART did not compromise immunological or virological outcomes among survivors after 48 weeks of treatment.
We have previously reported that TB is an important cause of early on-treatment mortality in this programme . In the present analysis, both prevalent and incident TB were associated with a greater than twofold greater mortality risk compared with those who remained TB free. Together these outcome data show that TB within this programme is associated with increased mortality risk, but that responses to ART are not compromised among survivors.
In summary, we have described an astounding burden of TB within this ART programme, with the cumulative proportion of 70% of patients having some history of TB (previous or active) by the end of the first year of ART and a high ongoing incidence rate after 3 years. Late initiation of ART is likely to be a key factor underlying this burden of previous, prevalent and incident TB. These data provide an important basis for defining future strategies to reduce the burden of TB associated with ART programmes.
The authors are grateful to Sister Marjorie Ntobongwana and the staff at the Hannan Crusaid antiretroviral clinic in Gugulethu and at the Desmond Tutu HIV Centre.
Sponsorship: Provision of ART at the programme was initially by Crusaid, London, UK and latterly by the Global Fund for Malaria, Tuberculosis and HIV/AIDS administered through the Provincial Government of the Western Cape. SDL is funded by the UK Wellcome Trust with grant 074641/Z/04/Z. LM, LGB and RW are all funded in part by the US National Institutes of Health through a CIPRA grant 1U19AI53217–01.
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