Introduction
Since the mid 1990s, use of highly active antiretroviral treatment (HAART) has been associated with a dramatic decline in HIV-associated morbidity and mortality in many high-income countries [1-3]. Suppression of viral replication permits both quantitative and functional reconstitution of the immune system [4-6]. Primary and secondary prophylaxis for opportunistic pathogens such as cytomegalovirus, Pneumocystis jirovecii, Mycobacterium avium complex (MAC), Toxoplasma gondii and Cryptococcus neoformans can be discontinued as functional host responses to these organisms are gradually restored [7-10]. The risk of recurrence of these opportunistic infections is generally very low once blood CD4 cell counts have reached stable levels > 200 × 106 cells/l [7]. Thus, substantial clinical benefit is achieved without full restoration of circulating CD4 cell numbers. It remains unclear, however, whether long-term viral suppression by HAART can effect complete quantitative and functional restoration of the immune system. Moreover, the optimal timing for initiation of HAART to preserve capacity for restoration remains to be determined.
The extent of immune restoration has important implications for the pattern of opportunistic infections occurring during HAART. Partial immune restoration may be sufficient to prevent disease from low virulence opportunistic pathogens such as disseminated MAC that develops exclusively in patients with profound immunodeficiency. However, more virulent pathogens such as M. tuberculosis (MTB) cause disease across the full spectrum of HIV-associated immunodeficiency [11] and restoration of MTB-specific functional immune responses that is only partial will result in a persistently heightened risk of tuberculosis (TB). The differential impact of HAART on host responses to pathogens has contributed to major changes in disease epidemiology in the HAART era. For example, TB is now the most frequent HIV-associated mycobacteriosis in Europe whereas the incidence of disseminated MAC was twice that of TB in the pre-HAART era [12].
Access to HAART is expanding in many low-income countries where the spectrum of opportunistic infections differs from that in high-income countries [13]. It is not yet clear how HAART will impact this burden of HIV-associated disease. TB is the opportunistic infection of prime importance and is the leading cause of morbidity and mortality among HIV-infected patients living in sub-Saharan Africa [14,15]. An estimated 31% of cases and 39% of TB deaths are attributable to HIV [16] and case series indicate that up to 80% of patients with TB are co-infected with HIV. In some townships in Cape Town, South Africa, HIV prevalence rates among antenatal women are approximately 30% and the incidence of TB in these communities has increased to around 1400/100 000 per year (unpublished data). Among HIV-infected patients with World Health Organization (WHO) stage 3 and 4 disease in Cape Town, the incidence of TB is extremely high with 24.1 cases per 100 patient-years [17].
The existing TB control strategy of case-finding and directly observed treatment of sputum smear-positive patients using short-course antituberculosis treatment is not proving adequate in countries with a high burden of HIV [18,19]. WHO has therefore formulated a strategic framework aimed at functional integration of control programmes for TB and HIV/AIDS [20]. HAART is one element within this framework. However, whether widespread use of HAART will prove an effective tool in TB control at the community level is not yet known.
The extent to which HAART will have an effect on TB control will be determined, in part, by the rate and extent to which functional immune responses to MTB are restored. Epidemiological, clinical and laboratory data all provide evidence that HAART restores host responses to MTB. These data include: (i) reductions in incidence of TB; (ii) alterations in the clinicopathological features of the disease; (iii) changes in skin test responses to purified protein derivative (PPD); and (iv) laboratory data showing improvements in functional responses of circulating lymphocytes. However, data are also emerging that suggest that immune restoration during HAART is incomplete and that an ongoing heightened risk of TB persists during long-term treatment. The magnitude of this risk is likely to reflect time-dependent changes in host immune function. Here we review these data and discuss the potential of HAART in TB control.
Impact of HAART on the incidence of TB
With one exception [21], studies conducted in countries with low [12,22-24] or high [17,25] prevalence of TB have shown that HAART is associated with substantial reductions in risk of TB in the order of 70-90% among HIV-infected cohorts (Table 1). In Cape Town, South Africa, this impact was significant across all the baseline immunological, clinical and socioeconomic variables, except for patients with blood CD4 cell counts >350 × 106 cells/l [17]. The greatest number of TB cases averted by HAART was in patients with baseline WHO clinical stage 3 and 4 and those with CD4 cell counts of <200 × 106 cells/l (Fig. 1). These studies suggest that expanding access to HAART may have a beneficial impact on TB control in high prevalence countries.
However, emerging data also suggest that although TB rates in treated cohorts decrease following initiation of HAART, rates remain persistently higher than among HIV-negative individuals. This observation has been made in countries with a low and high burden of TB. Among the Swiss cohort, in which the median pre-HAART CD4 cell count was 188 × 106 cells/l, an elevated though diminishing rate of TB was observed for at least the first 6 months of HAART [22]. Certainly a lag time exists between the initiation of HAART and the restoration of sufficient levels of anti-mycobacterial immune function that are able to exert a protective effect. High but diminishing rates of TB after commencement of HAART are likely to reflect time-dependent reductions in residual immunodeficiency, the duration and extent of which may well depend on the nadir CD4 cell count. Immune reconstitution disease (IRD) may also contribute to TB incidence in the initial months of HAART (see below); active but subclinical TB among profoundly immunodeficient patients may manifest as host immune responses are restored [26,27].
An increased rate of TB during HAART is not simply a short-term phenomenon. An observational study in Italy of HIV-associated TB in the era of HAART described factors associated with 271 incident cases [28]. Of these, 30.3% were receiving HAART prior to TB diagnosis and this treatment had been prescribed for a median of 27 months. The median blood CD4 cell count at diagnosis of TB (220 × 106 cells/l) was significantly greater than the level pre-HAART (80 × 106 cells/l) and was also significantly greater than the median CD4 cell count of HIV-infected patients who developed TB but were not receiving HAART (109 × 106 cells/l). This finding suggests that substantial restoration of CD4 cell numbers had occurred among the majority of patients receiving HAART by the time TB was diagnosed.
Similar observations are also being reported from the developing world. TB was the most common opportunistic infection in a cohort of patients with advanced immunosuppression receiving HAART in Thailand [29]. Among patients with WHO stage 3 and 4 disease in Cape Town, South Africa, the incidence of TB during HAART was 4.6 cases/100 patient-years; this is approximately 10-fold greater than the incidence among HIV-negative individuals in the same community [17]. A pilot community-based antiretroviral project in Cape Town reported high rates of TB during the first year of HAART [30]. Our current observations at the same site are that among patients referred for HAART, approximately 5% have active TB on pre-HAART screening and a further 10% of patients develop TB after initiation of HAART during the first year of follow up (unpublished data) despite excellent treatment compliance [31]. Thus, although TB rates are markedly reduced by HAART, TB still represents a substantial burden of disease during this treatment, especially in communities with high TB prevalence.
Impact of HAART on the manifestations of TB
Clinical and radiological presentation
The impact of HIV on the clinicopathological features of TB is well documented [32,33]. HIV-associated immunodeficiency results in an increased frequency of cutaneous anergy to PPD and increased rates of extrapulmonary and disseminated disease [32,34]. Radiographic appearances of pulmonary TB in patients with HIV-1 coinfection are more frequently atypical, reflecting impaired tissue inflammatory responses to infection [35,36]. All-cause mortality is also greatly increased and is directly related to the degree of immunodeficiency [37]. However, as might be expected, HAART modifies the clinicopathological features of TB as immune function is restored. HAART increases the frequency of the typical post-primary radiographic pattern of pulmonary TB (Fig. 2) [38,39], rates of PPD skin test conversion (Fig. 3) are higher [40,41] and patient survival is increased [38]. The frequency of extrapulmonary disease might also be expected to decrease among patients receiving HAART, but the single study examining this possibility was not of sufficient size for full evaluation [38].
Immune reconstitution disease
The most striking evidence of restoration of functional immune responses to MTB is that provided by reports of IRD, also known as the immune reconstitution inflammatory syndrome. IRD is an adverse consequence of restoration of immune responses during the initial months of HAART [26,27]. Previously subclinical infections are 'unmasked' or pre-existing partially treated opportunistic infections clinically deteriorate as immunopathological host inflammatory responses are 'switched on' during HAART. IRD associated with HAART was originally described in patients with MAC infection and who were receiving zidovudine monotherapy [41]. Presentation with IRD was temporally associated with development of positive PPD skin test responses (Fig. 3) among patients with previous cutaneous anergy, providing evidence of restoration of delayed type hypersensitivity (DTH) responses.
IRD associated with MTB was not reported until after the development of HAART [42]. Among 86 published cases of TB-associated IRD, the median duration of HAART prior to development of IRD was just 4 weeks, illustrating the extraordinary rapidity with which HAART reverses HIV-associated paresis of immune responses to MTB [26]. Among these cases, the median blood CD4 cell count increased from a pre-treatment nadir of 5 × 106 cells/l [interquartile range (IQR), 26 × 106 -103 × 106 cells/l] to 205 × 106 cells/l (IQR, 110 × 106 -298 × 106 cells/l) at the time of IRD diagnosis. Typically the plasma viral load is markedly reduced by the time of IRD onset, reaching the lower limit of detection in approximately half the patients. Some patients develop IRD associated with TB within 2 weeks of initiating HAART, even prior to an increase in CD4 cell count. This finding is likely to reflect the rapid restoration of functional immune responses that accompanies rapid reductions in viral load.
MTB-associated IRD most commonly presents with fever, lymphadenopathy or worsening respiratory symptoms. A wide spectrum of other manifestations include development of pleural effusions, ascites, hepatosplenomegaly [43], psoas abscesses [44], intra-abdominal abscesses [45], epididymo-orchitis [43], central nervous system lesions [46], skin lesions [42], acute renal failure [47] and hypercalcaemia [48]. These observations indicate that HAART rapidly restores anti-mycobacterial immune function in diverse anatomical compartments and suggests that HAART permits recruitment and proliferation of effector cells at those sites. Rapid reversal of immune function may trigger severe immunopathology in patients with subclinical or partially treated TB. Life-threatening clinical manifestations include acute respiratory failure from widespread pulmonary alveolitis [49,50] and major airway obstruction due to rapidly expanding intra-thoracic lymph nodes (Fig. 4) [51]. Systemic corticosteroid treatment plays a key role in the control of severe manifestations.
Histopathological examination of tissues involved in IRD associated with mycobacteria may show suppuration and a degree of necrotizing inflammation that is unusual in the context of profoundly immunocompromised patients [52-54]. It is likely that the rapidity with which immune responses are restored and the lack of compensating immunoregulatory mechanisms result in the uncontrolled tissue-damaging responses that characterize IRD. Further indirect evidence that HAART restores the ability to form physiologically functioning granulomas (Fig. 5) is provided by reports of hypercalcaemia during mycobacterial IRD [48,55]. Hypercalcaemia is a well-recognized complication of mycobacterial infection, arising as a result of production of 1,25-dihydroxycholecalciferol in functional granulomas [56]. Elevated serum levels of 1,25-dihydroxycholecalciferol and hypercalcaemia during mycobacterial IRD is therefore likely to reflect restoration of the ability to form physiologically functioning granulomas [48].
Mechanisms and extent of immune recovery during HAART
The development of HAART using combinations of reverse transcriptase and protease inhibitors in 1995 marked the dawn of a new era in HIV management. For the first time, robust suppression of plasma viral load was associated with substantial immune restoration [4-6]. HAART usually leads to a >90% reduction in plasma viral load within the first weeks of treatment [57]. Three principal laboratory parameters provide evidence of subsequent immune recovery during HAART: (i) quantitative restoration of immune cells; (ii) normalization of cell phenotype; and (iii) recovery of immune cell function. Here, we initially consider immune recovery in general and later review the data that specifically relate to immunity to MTB.
Changes in CD4 cell counts
The CD4 cell count increases that accompany the viral load reductions occur in two principal stages. A rapid increase in the number of circulating CD4 cell lymphocytes within 1-2 weeks of starting HAART and continuing over the first 2-3 months largely represents a redistribution of activated CD45Ro memory cells previously sequestered in lymphoid tissue, and a generalized reduction in apoptotic cell death [4,5]. This initial increase coincides with the period within which manifestations of IRD are most frequently observed. A slower second phase of CD4 cell expansion persists over subsequent months and may continue for years. This observation represents expansion of naive CD45RA cells as thymic function is restored and results in the long-term sustained rise in CD4 cell count. This sustained increase in CD45RA cells correlates with the magnitude of viral load suppression and its stability over time [5].
After 2-4 years of HAART, mean or median increases in CD4 cell counts are approximately 200-400 × 106 cells/l [58-62]. The increases predominantly occur in the first 1 or 2 years with comparatively smaller gains thereafter. In a multicentre study of 314 HIV-infected homosexual men in the USA, blood CD4 cell counts were observed to plateau between 2 and 3.5 years of HAART [63]. In a prospective cohort of 237 HAART-naive patients, with a baseline median CD4 cell count of 175 × 106 cells/l and viral suppression maintained for more than 1 year, more sustained CD4 lymphocyte increases were observed during HAART [61]. After an initial rapid increase in median CD4 cell count of 97.2 × 106 cells/l in the first month, the rate of CD4 cell increase sequentially diminished thereafter, with rates of 11.6 × 106 cells/l/month from year 1 to year 2 and an estimated rate of 5.4 × 106 cells/l/month at year 2. A more recently published study with 6 years follow-up of 20 selected patients found that CD4 cell counts continued to rise, albeit slowly, during years 3-6 of HAART [64].
While viral suppression is a key determinant of long-term CD4 cell recovery [62], the nadir CD4 cell count at the time HAART is started may also be an important factor. CD4 cell repletion in both blood and lymphoid compartments occurred during the first year of HAART among patients with early disease and baseline CD4 cell counts > 400 × 106 cells/l [65]. In contrast, CD4 cell numbers had not normalized after nearly 3 years of follow up among patients with severely depleted CD4 cell counts at initiation of treatment [66]. A more recently published study of a small group of patients, however, showed that CD4 cell rises may continue for up to 6 years despite severe pre-treatment CD4 cell depletion [64]. Kaufmann et al. found that older age and lower nadir CD4 cell counts were both predictive of a poorer CD4 cell recovery [59] and these factors may be related to persistent impairment of thymic function [67]. The extent of CD4 cell recovery may also be related to low-level viraemia and pro-viral DNA levels [68].
It can be concluded that responses to HAART fall within a spectrum. Some patients have little or no rise in CD4 cell counts despite complete viral suppression [69,70]; others may have CD4 cell counts that plateau at suboptimal levels [63] and a proportion have persistent CD4 cell increases over many years [64].
Changes in CD4 cell phenotype
The phenotype of circulating T lymphocytes in HIV-infected patients reflects immune competence. Numbers of studies show that circulating CD4 and CD8 lymphocyte subsets are only partially restored in the first year of HAART [4,71,72]; as with total CD4 cell counts, however, changes in these subsets may continue for many years [64]. Although expression of the cellular activation markers, HLA-DR and CD38, by CD4 and CD8 lymphocytes decreases substantially during the first year of HAART, these populations remain abnormally activated for up to 6 years of HAART [60,64]. Furthermore, the number of circulating CD4 and CD8 lymphocytes that express CD28, a co-stimulatory molecule important in T-cell responses to antigen, do not increase to normal levels during long-term HAART even among those who normalize their CD4 cell counts [73]. Additionally, HLA-DR and CD38 expression by CD8 lymphocytes remain elevated among patients starting HAART with advanced disease. Overall, among patients with virological suppression, the likelihood of phenotypic normalization of circulating lymphocytes diminishes the lower the nadir CD4 cell count [73].
Changes in CD4 cell function
In addition to demonstrating quantitative cellular restoration and improvements in immune cell phenotype, a number of studies has also described improvements in immune function during HAART [4,60,72-74]. In general, in vitro T-cell proliferative responses to recall antigens and mitogens improve during treatment [4,60,72] and cytokine responses shift from a predominantly type 2 to a type 1 pattern, with increases in interferon (IFN)-γ and interleukin (IL)-2 production [75-77]. Later increases in circulating CD45RA naive lymphocytes are associated with reversal of HIV-associated defects in the T-cell receptor (TCR) repertoire [78,79] and restoration of immune responses to neoantigens [74]. DTH responses to antigens assessed by skin testing also improve and correlate with the magnitude of viral load reduction [80].
It is clear, however, that long-term functional deficits persist during HAART. Imbalances in cytokine profile and TCR repertoire disruptions persist for at least 1 year of treatment [77,79] and antibody responses to vaccines, such as pneumococcal vaccine, remain suboptimal during long-term treatment [81]. Lange et al. conducted a detailed assessment of functional T-cell responses among patients who had a wide spectrum of nadir blood CD4 cell counts, good virological responses and normalized CD4 cell counts on long-term HAART [82]. Antibody responses to immunizations, lymphocyte proliferation in vitro and DTH responses to vaccine antigens were evaluated. Despite normal CD4 cell counts, functional immune responses remained impaired and the degree of impairment was directly related to the nadir but not current CD4 cell count [73].
Restoration of MTB-specific immune responses during HAART
Few studies examine restoration of anti-mycobacterial and MTB-specific immune responses. Among a cohort of patients with a history of disseminated MAC infection, proliferation of peripheral blood mononuclear cells (PBMC) in response to MAC antigen in vitro showed stimulation indices of ≥ 3 among 46% of patients prior to HAART and among 77% of patients after 6 months of HAART [83]. There was no further increase in the proportion of patients with positive responses at 12 months and the proportion of positive responders was similar to that among HIV-negative control subjects. Similar data are reported by Wendland et al. [80]. Restoration of proliferative responses to MAC and M. xenopi during the first 6 months of HAART is temporally associated with development of IRD [84].
Proliferation of PBMC stimulated in vitro with PPD is also enhanced during receipt of HAART; the proportion of positive responders increases steeply during the first 6 months [4,72,80] and is sustained at 12 months [72]. Li et al. showed that not just the proportion of responders but also the magnitude of cell proliferation increases markedly [72]. In a prospective cohort of 10 patients followed up at 2-monthly intervals over 1 year, Schluger et al. found that PBMC stimulated with the laboratory strain MTB H37Ra also produced a steadily increasing amount of IFN-γ [85]. However, responses at 1 year were markedly less than those among HIV-negative control groups with either positive or negative PPD skin test responses. Furthermore, production of IL-2 and IL-12 increased minimally.
Hsieh et al. prospectively studied 13 patients during HAART for 1 year, using expression of the lymphocyte activation marker CD69 following in vitro stimulation of PBMC with PPD as a correlate of MTB-specific immune responses [86]. In a majority of patients, the percentage of CD4 cells and CD8 cells responding to PPD increased during the first year of HAART. However, although substantial increases in CD4 cell count were observed in all patients, a small group of patients failed to restore these responses after 1 year of HAART. These patients were more likely to have nadir CD4 cell counts of <50 × 106 cells/l compared to those who had good restoration of responses [86]. This suggests that delaying initiation of HAART in chronic HIV infection may lead to long-term impairment of functional immune responses to MTB.
Quantitative restoration of MTB-specific IFN-γ-secreting cells during HAART has not been investigated. Hengel et al. described a single patient with disseminated MTB infection and HIV infection who started antituberculosis treatment and HAART concurrently [87]. The proportion of peripheral blood MTB-specific CD4 cells staining positively for IFN-γ increased from 8.6% on day 11 to 33% on day 95 of treatment. To what extent this remarkable expansion of MTB-specific T cells represented an effect of HAART or an effect of antituberculosis treatment is unknown. Studies are needed to determine the extent to which MTB-specific T cell clones are restored during HAART.
HAART as a TB control strategy
Although finding and curing active TB cases remains the principal intervention for TB control in high HIV prevalence settings [88] it is nevertheless failing [18,19]. A multifaceted approach is therefore required [20]. The extent to which HAART will play a role within such a framework has yet to be determined and will depend on: (i) the efficacy of HAART in preventing TB; (ii) the population coverage; and (iii) the extent to which HAART prolongs life. It seems likely that if HAART is unable to completely restore MTB-specific immune responses and thereby reverse the risk of TB to levels present prior to acquisition of HIV infection, then the overall improvement in patient prognosis will result in an expanding survivor cohort with a chronically heightened susceptibility to TB. Thus, when considering the effect on TB control, the huge short-term benefit of HAART in reducing TB risk for the treated individual is unlikely to be reflected at the community level in the long term.
Williams and Dye (2003) modelled the potential impact of HAART on TB incidence, combining data on rates of CD4 cell decline during HIV infection, relative incidence of TB at different CD4 cell counts and the known impact of HAART on TB incidence [89]. They calculated that if HAART were given to patients with CD4 cell counts < 200 × 106 cells/l with complete coverage and perfect compliance; the cumulative incidence of TB would be decreased by just 22% over 20 years. Conversely, to reduce TB incidence by 50% over 20 years with 85% effective coverage, use of HAART would have to be greatly expanded to include patients with CD4 cell counts < 500 × 106 cells/l-an unrealistic proposition [89]. The small long-term impact of HAART on TB incidence is explained by the fact that HAART reduces the risk of TB but also extends life expectancy markedly. Thus, HAART-treated individuals develop TB at a lower rate but over a longer period of time.
The modelling data of Williams and Dye is based upon several assumptions. Calculations assume that HAART restores functional responses to MTB to levels present in the early stages of chronic HIV infection. However, at present there are insufficient data to know whether this is the case during long-term HAART. It is likely that there are gradual time-dependent changes in immune function, which are paralleled by time-dependent changes in patient susceptibility to TB. The modelled predictions are based on a 20-year time-scale whereas data on efficacy of HAART in reducing TB incidence are derived from studies with a much shorter duration of follow up. Moreover, the effect of HAART on rates of TB transmission and reinfection are not taken into account. Future data may help to further validate these modelling calculations.
The extent to which HAART restores long-term MTB-specific immune responses is critical and will be a key determinant of the extent to which HAART is able to contribute to TB control at the community level. Strategies that optimize MTB-specific immune restoration need to be explored. Current data indicate that early initiation of HAART may promote more complete immune restoration. Thus, in communities with high TB burden, early initiation of HAART may have an important long-term benefit in reducing TB rates. Further adjunctive strategies might also be explored to boost the restoration of MTB-specific immune responses. Such interventions might include use of bacille Calmette-Guerin vaccination during HAART or co-administration of cytokine therapy such as IL-2 [90]. Prophylaxis with isoniazid during HAART remains an alternative strategy.
The challenge of incident TB during HAART
Since HAART fails to reduce the incidence of TB to levels in HIV-negative individuals, a substantial rate of TB persists during HAART. This fact presents a major challenge to HAART programmes, especially in communities with a high prevalence of TB. In Cape Town, for example, our experience is that these problems are many-fold: (i) TB is an ongoing substantial cause of morbidity and mortality that consumes already over-stretched health resources; (ii) development of TB despite HAART undermines patient confidence in HAART; and (iii) concurrent treatment with HAART and anti-TB drugs presents difficulties associated with pill burden, patient adherence to treatment, pharmacokinetic interactions and overlapping toxicities [91]. An additional concern is the potential for nosocomial transmission of TB at HAART clinics; this is as yet unquantified. Thus, although the clinical benefits of HAART are undoubtedly huge, our experience at a successful community-based HAART project in Cape Town is that incident TB remains a major challenge among treated patients.
Conclusions
HAART has a remarkable impact on HIV/AIDS-associated morbidity and mortality and has greatly extended the prognosis of people living with the virus. We have reviewed how suppression of viral replication permits gradual restoration of lymphocyte numbers, phenotype and function over many years. The extent to which CD4 cell counts are restored is variable. Current data, however, show that even among those patients who develop full numeric restoration of circulating CD4 cell lymphocytes, phenotypic abnormalities and functional defects persist. Persistent abnormalities are most likely when immunodeficiency is more advanced at the time of initiation of HAART (Table 2).
Long-term deficits in MTB-specific immune responses are likely to be an important factor contributing to the higher than expected incidence of TB among patients receiving HAART. Suboptimal restoration of MTB-specific immunity hinders the extent to which HAART may play a role in TB control at the community level since patients receiving HAART survive longer and yet maintain a chronically heightened risk of TB. Thus, although the benefit of HAART to the individual in reducing TB risk is great, the impact at the community level is much less. Current modelling analysis predicts that HAART will have a more limited impact on TB incidence than might have been anticipated (Table 2).
Future epidemiological studies need to more clearly define the long-term incidence of TB during HAART in prospective study cohorts in low-income countries. The impact of HAART on TB epidemiology at the community level should also be studied, using careful TB surveillance to determine the effect on both the burden of disease and patterns of TB transmission within the community. The extent to which transmission of TB occurs at antiretroviral clinics also needs to be assessed. Laboratory studies should prospectively define the rate and extent to which functional immune responses to TB are restored during long-term HAART. This would permit factors associated with suboptimal restoration to be identified and strategies to augment MTB-specific immune responses to be explored. The timing of initiation of HAART may prove to be the most important factor in this respect and early initiation of HAART may lead to long-term benefits in TB risk reduction. However, widespread early initiation of HAART in low-income countries would be very costly in health resources and detailed cost-benefit analyses are required. Nevertheless, as access to HAART expands in low-income countries and treatment recommendations are established and refined, the long-term effect of HAART on TB control needs to be carefully evaluated.
Acknowledgements
Sponsorship: S.D. Lawn is funded by the Wellcome Trust, London, UK with grant 074641/Z/04/Z.
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