Introduction
The association between HIV infection and tuberculosis is complex and bi-directional. The epidemiological effects of HIV infection on primary infection, re-infection, and reactivation disease with Mycobacterium tuberculosis have been well documented [1-5]. However, the evidence concerning the effect of tuberculosis on the progression of HIV-associated immune deficiency and disease is less clear. Although there seems to be a consensus among basic scientists that tuberculosis enhances HIV replication, the significance of this laboratory observation for clinical medicine and public health is more open to debate. In this review current laboratory, epidemiological and clinical data concerning the effects of tuberculosis on HIV disease progression are examined, and conclusions are drawn about further research requirements and public health implications.
Laboratory observations
Considerable in-vitro laboratory data support the concept that active tuberculosis leads to increased HIV replication. In addition, several clinical studies have shown that patients with active tuberculosis have an increase in HIV viral load compared with HIV-infected persons without tuberculosis.
Cellular activation and upregulation of pro-inflammatory cytokines lead to increased HIV replication
Cellular activation results in enhanced HIV replication mediated by the release of pro-inflammatory cytokines, IL-1, IL-6 and TNF-a. In particular, the upregulation of TNF-a results in a marked increase in HIV replication, both in monocytes and in lymphocytes [6-11]. This TNF-a-mediated effect can be specifically reversed with antibodies to TNF-a, or with TNF-a inhibitors such as thalidomide or pentoxyfilline [12-14]. The mechanism by which TNF-a enhances HIV replication is via a DNA binding protein, nuclear factor kappa B (NFk-B), which binds to an enhancer site at the 5′ end of the long terminal repeat of HIV [11,12,15-20].
Cellular activation and cytokines in Mycoplasma tuberculosis and HIV co-infection
The effect of tuberculosis on HIV replication is mediated indirectly by cytokines. Active disease, as opposed to latent M. tuberculosis infection, leads to cellular activation and cytokine release, which in turn results in enhanced viral replication [21,22]. TNF-a is produced in response to mycobacterial proteins and lipoarabinomannan [23-26]. It is synthesized in increased amounts in active tuberculosis [27,28], and is an integral part of the host immune response by permitting granuloma formation and preventing overwhelming infection [29]. Active M. tuberculosis infection also stimulates the release of other pro-inflammatory cytokines, IL-1 and IL-6, in both animal models and in tuberculosis patients [25-34]. M. tuberculosis upregulates the genes encoding these cytokines in cultured monocytes from patients with tuberculosis [27,35].
In-vitro studies have shown that mononuclear phagocytic cells infected with HIV produce up to threefold increased amounts of p24 antigen when co-infected with M. tuberculosis [36]. Both M. tuberculosis and purified protein derivative have been shown to stimulate HIV long terminal repeat-driven transcription in lymphocytes and monocytes acutely and chronically infected with HIV, an effect mediated both by pro-inflammatory cytokines and the NFk-B enhancer element [36-38].
Clinical correlates of in-vitro cytokine data
A number of clinical studies provide data correlating with these in-vitro data. HIV-negative patients with tuberculosis show a doubling in serum and cellular markers of immune activation such as TNF-a, beta-2 microglobulin, and neopterin compared with controls without tuberculosis. This phenomenon is even more marked in HIV-positive patients, who had threefold increases in the levels of these markers [39]. Similar observations were made in HIV-infected patients with tuberculosis from Uganda, who had three- to 10-fold increases in antigen-induced blastogenesis and TNF-a, as well as higher levels of beta-2 microglobulin compared with HIV-positive and HIV-negative controls without tuberculosis [33]. Monocytes from patients with tuberculosis have been shown to be more receptive to productive infection of HIV than cells from age-matched controls, the enhanced susceptibility being attributed to an increase in the number of activated cells in the tuberculosis group [40]. A double-blind, placebo-controlled trial of the TNF-a antagonist thalidomide, in patients from Thailand, resulted in reduced TNF-a levels in treated patients with HIV-associated tuberculosis [41].
Viral load and CD4 lymphocyte counts in HIV-infected patients with tuberculosis
Bronchoalveolar lavage studies in three HIV-infected patients with pulmonary tuberculosis showed higher levels of HIV p24 antigen in lobes with active tuberculosis than in those without, in one case even exceeding the levels in the plasma [36]. Although this demonstrates increased levels of HIV at the site of active tuberculosis, this could result from the marked cellular recruitment that occurs in response to a focus of inflammation.
The most relevant data come from studies of HIV-1 plasma RNA in HIV-infected persons before, during, and after an episode of tuberculosis [42]. A five- to 160-fold increase in viral load was noted during the acute phase of M. tuberculosis disease (n=7), with reductions in levels after successful treatment. The same authors demonstrated in vitro that M. tuberculosis induced HIV replication in CD8 T-cell-depleted cultures of primary peripheral blood mononuclear cells and lymph node mononuclear cells, but this was restricted to tuberculin-positive individuals, implicating a role for antigen-specific memory T cells in facilitating HIV replication. The trial of thalidomide, the antagonist of TNF-a, in Thai patients with tuberculosis, showed reduced levels of HIV in treated patients, but the clinical significance of these observations remains to be determined [41]. Unlike in active tuberculosis, patients with asymptomatic M. tuberculosis infection had similar rates of decline in CD4 lymphocytes and similar levels of HIV viral load as patients without latent infection [43].
Tuberculosis itself may cause reversible CD4 lymphocyte depletion, possibly by the sequestration of CD4 cells in sites of active disease [44-47]. This has been studied in patients with tuberculous pleural effusion, but might be substantial in persons with disseminated tuberculosis. When idiopathic CD4 lymphocyte depletion was first recognized as an entity, mycobacterial infections were a frequent association, and in Cote d‚Ivoire approximately 4% of HIV-negative tuberculosis patients had CD4 lymphocyte counts of less than 300¥106/l [48,49]. Although the biological relevance of tuberculosis-induced CD4 lymphocyte depletion is uncertain, it is possible, presumably, that this phenomenon may potentiate the CD4 lymphocyte destruction resulting from increased HIV replication.
Virological changes in other opportunistic infections
Many of the laboratory abnormalities and changes described above do not seem to be specific to tuberculosis. Increased levels of HIV-RNA have been documented in a number of opportunistic illnesses as well as in other circumstances, including Pneumocystis carinii pneumonia, bacterial pneumonia, acute herpes simplex outbreaks and other illnesses [50-53], and after immunization with some common recall antigens or against infections such as influenza [54-56]. The significance of such acute changes or their long-term effects remains uncertain.
Epidemiological observations
Epidemiological data examining the effect of tuberculosis on the natural history of HIV infection show results that are apparently contradictory. Studies comparing outcome in HIV-infected patients who developed tuberculosis with that in patients who did not suggested that tuberculosis was associated with an adverse outcome [57,58]. On the other hand, compared with other HIV-associated opportunistic infections, tuberculosis generally carries a more favourable prognosis [59-66]. To some extent, these observations reflect differences in the specific phrasing of questions to be addressed in different research protocols.
Studies examining survival from initial AIDS diagnosis
A number of studies have examined large cohorts of HIV-infected persons to assess survival from initial AIDS diagnosis and risk factors for adverse outcome. Although there were exceptions and substantial differences between countries, crude data from the United States, Brazil, and Europe showed that patients with tuberculosis as the initial AIDS-defining illness had a reduced risk of death and better median survival times than persons developing P. carinii pneumonia (Table 1) [59-61,63-66]. In addition, in most of those studies, the proportions of persons who survived 12 and 36 months were greater for persons with tuberculosis as the initial AIDS-defining condition than for those who first developed P. carinii pneumonia. These survival differences may have been accentuated by the inclusion of pulmonary tuberculosis as an AIDS-defining condition in the 1993 expanded AIDS case definition, analogous to the ‚lead-time‚ bias observed in cancer epidemiology when earlier diagnosis may be interpreted as longer survival. Before 1993, only extrapulmonary tuberculosis was considered an AIDS-defining illness, and extrapulmonary disease is associated with more advanced immune deficiency [67].
Adjusted analyses examining the risk of death in patients according to their initial AIDS-defining condition are summarized in Table 2. In the AIDS in Europe Study, persons with extrapulmonary tuberculosis had a 43% lower risk of death compared with those who developed P. carinii pneumonia after adjusting for different confounders [61]. In Spain, multivariate analyses of factors affecting survival in AIDS patients showed that the development of extrapulmonary tuberculosis carried a lower risk of death (38 and 53%) when compared with other conditions such as P. carinii pneumonia or Kaposi‚s sarcoma [65,66]. In a multivariate analyses which included the CD4 cell counts at initial AIDS diagnosis, patients with AIDS in London who presented with either pulmonary or extrapulmonary tuberculosis had a survival advantage (64%) over those presenting with diagnoses other than P. carinii pneumonia or Kaposi‚s sarcoma [68].
All the studies quoted above were retrospective cohort studies of persons with prevalent HIV infection of unknown duration. Tuberculosis is a treatable disease that tends to occur relatively early in the course of HIV disease, at median CD4 lymphocyte counts in excess of 200¥106/l [69-71], and this may contribute to the more favourable crude survival rates. However, because in at least one study [68] survival was also better after adjusting for CD4 lymphocyte count, tuberculosis may be a milder disease or have less influence on the course of underlying HIV infection than other opportunistic infections.
Studies assessing HIV disease progression after tuberculosis
Broadly, two types of analyses have been performed. First, some researchers have compared outcome in HIV-infected patients who developed tuberculosis with that in patients who did not develop the disease, after appropriate matching, stratification, or adjustment for confounders such as previous opportunistic illness or level of CD4 lymphocyte count. A second approach has been to model incident tuberculosis or other AIDS illnesses as time-dependent covariates, thus accounting for the competitive risks of adverse outcome from other and subsequent opportunistic events.
Whalen et al. in the United States [57] and Leroy et al. in France [58] studied the survival and incidence of new opportunistic illnesses in HIV-positive individuals who had tuberculosis compared with a group of persons who remained tuberculosis free at the end of the study period. Patients and controls were matched on CD4 lymphocyte count as well as on a history of previous opportunistic illness. In both studies, patients who developed tuberculosis had an increased risk of death and shorter median survival than persons not developing tuberculosis. The incidence of new opportunistic infections was higher in patients who had developed TB compared with those who had not, but this difference was not statistically significant in either of the studies [57,58].
Three studies have modelled tuberculosis and other AIDS events as time-dependent variables allowing changing risks for adverse outcome to be modelled in the face of different incident events [63,72,73]. Perneger et al. [72] examined data from the AIDS in Europe Study, and showed that incident tuberculosis in patients with a previous AIDS diagnosis was an unfavourable event, but they did not compare its impact with that of other AIDS-defining illnesses [72]. Mocroft and colleagues, [62] also using the AIDS in Europe data set, and Petruckevitch and colleagues [63], showed that the incidence of tuberculosis was unfavourable compared with no incident AIDS event, but that of all incident AIDS events, tuberculosis was associated with the lowest risk of death and the most favourable survival rates [63,73]; and patients with tuberculosis had a lower incidence of subsequent AIDS-defining conditions than persons with other initial AIDS diagnoses [63].
Few data exist on serial CD4 lymphocyte decline over time after tuberculosis, but two studies argue for no differences between those with and without tuberculosis. Leroy et al. [58] found that differences in incidence of less than 50 CD4 cells/mm between patients with and without tuberculosis were not statistically significant (P=0.09), and Petruckevitch et al. [63] examined the mean rate of decline of CD4 lymphocyte counts, and found no statistically significant differences between groups (P=0.77) [63].
Ecological observations
If tuberculosis adversely affects the natural history of HIV infection, then disease progression would be expected to differ in different areas of the world according to the incidence of tuberculosis in HIV-infected persons, but this does not seem to be the case. Tuberculosis accounts for one third of deaths in HIV-infected persons in sub-Saharan Africa, and is also more frequent as an AIDS-defining condition in South America, South and South-East Asia, and Southern Europe than in the industrialized countries of Europe and North America [5,74-78].
Differential survival with AIDS by country or region seems to be largely related to the quality of medical care available, and there is little evidence that the progression of disease in Africa is inherently faster than elsewhere. Specific diseases such as tuberculosis and bacterial infections occur at relatively high CD4 lymphocyte counts, but evidence that CD4 lymphocyte decline occurs at a faster rate in some than in other regions is lacking.
Grant and colleagues [79] reviewed the literature on the natural history of HIV infection in Africa and concluded that disease progression appeared to be similar in industrialized and developing countries. Del Amo et al. [68] compared the natural history of HIV/AIDS in Africans (most of whom were recent immigrants and in whom tuberculosis was the dominant opportunistic infection) and non-Africans in London, and found similar rates of disease progression after adjusting for differences in previously known confounders. In Spain, tuberculosis is the commonest AIDS-defining condition and median survival times are similar to those observed in central/northern Europe and North America [59,65,66,68]. If tuberculosis does affect the progression of immune deficiency in HIV-infected persons, it is difficult to discern this at a population level.
Intervention studies
It is believed that most of the excess mortality in HIV-infected patients with tuberculosis results from other complications of HIV disease rather than from tuberculosis itself. If tuberculosis does accelerate HIV progression, then its prevention and/or correct treatment would be expected to result in a more favourable outcome.
Results are now available from at least four placebo-controlled trials [80-83] of preventative therapy in HIV-infected persons, three conducted in sub-Saharan Africa. Although the incidence of tuberculosis was reduced, survival was not shown to be improved except in the small study from Haiti [80], which claimed a reduced mortality from AIDS. However, AIDS was diagnosed clinically on the basis of the HIV wasting syndrome, and a substantial proportion of such patients in developing countries have disseminated tuberculosis at autopsy [84]. Reduced mortality may, therefore, simply have indicated a reduced incidence of tuberculosis rather than a reduced progression to other AIDS-associated illnesses. A recently published meta-analysis [85] on the effect of preventative therapy for tuberculosis in HIV-positive patients concluded that although prophylaxis was associated with a reduction of 43% in the incidence of tuberculosis, overall mortality was not reduced. A sub-analysis of only purified protein derivative-positive patients [86] showed that in this group, the reduction of tuberculosis was greater (68%) and mortality was significantly lower (27%).
Limitations of basic science and epidemiological studies
Laboratory and in-vivo studies indicate that tuberculosis increases immune activation and enhances HIV replication, and tuberculosis in HIV-infected persons has a surprisingly high mortality rate. In contrast, tuberculosis in most studies had a favourable outcome compared with other opportunistic infections, the immunological and virological changes associated with tuberculosis also occur with other opportunistic infections in HIV-infected persons, and preventing tuberculosis has generally not been shown to improve survival from HIV disease. Relevant questions include the applicability of laboratory data in vivo, the temporal sequence of events leading to increased HIV viral load and immunological markers in persons with HIV-associated tuberculosis, the nature of the epidemiological comparisons that have been made, and the non-specificity of some of the major laboratory and clinical perturbations in HIV-infected persons with tuberculosis.
A handicap in the understanding of events in HIV-associated tuberculosis is a lack of correlative markers of protection against tuberculosis, and uncertainty about whether disease is caused by reactivation of M. tuberculosis, new infection, or re-infection. Much tuberculosis, including in areas where rates of co-infection with HIV and M. tuberculosis are highest, such as in sub-Saharan Africa, is caused by reactivation [87], and this provides the rationale for the use of antituberculous preventative therapy. However, other mechanisms such as recent infection and re-infection also contribute to the disease burden, especially in developing countries where there is on-going transmission, and may contribute to the less than perfect efficacy of preventative therapy for tuberculosis [86,88]. Persons who reactivate tuberculosis infection are probably different from co-infected persons who do not, suggesting that matching on previous CD4 lymphocyte count and medical history may not be adequate to exclude pre-existing differences among cases and controls in some of the frequently cited studies reviewed above. The different immunological and virological host terrain in HIV-infected persons suffering primary infection or re-infection as opposed to reactivation tuberculosis also needs to be explored.
Increased plasma HIV-RNA levels are now recognized as a major risk factor for progression to AIDS and death in HIV-infected persons [89]. Understanding of the temporal sequence of viral load measurements in persons with HIV-associated tuberculosis is limited and sequential data from greater numbers of people would be helpful. A technical limitation of some studies on African subjects is that some assays for plasma HIV-RNA are insensitive for non-B subtypes of HIV [90]. The suggestion that inherent rises in plasma HIV-RNA precede increased markers of immune activation and increased risk for opportunistic infections such as tuberculosis will need to be excluded as an alternative hypothesis. Another scenario is that of a vicious cycle in which an unmeasured predisposition to HIV progression increases the risk of tuberculosis, which in turn accelerates HIV replication and disease.
To conclude, interpretation of the epidemiological data is influenced by the choice of the comparison group. Compared with HIV-infected persons who do not develop disease, those with incident tuberculosis have an increased risk of death; this is not surprising, however, because persons with other AIDS-associated opportunistic infections have a worse prognosis than those who remain AIDS free, or those with subsequent illnesses compared with those without. The underlying question concerns the true comparability of persons developing tuberculosis with those who do not, even after maximal adjustment for known prognostic factors.
Implications and future research
A better understanding of the temporal sequence of laboratory and clinical events could be obtained from frequent measurements of plasma HIV-RNA, CD4 lymphocyte count, and markers of immune activation in HIV-infected persons with and without incident tuberculosis followed over time, ideally in seroconverter cohorts. A nested case-control study within such a cohort followed for some other purpose would offer the most efficient way of evaluating risk factors and outcomes related to incident tuberculosis. A further study design would have been the same regular measurement of these laboratory parameters, viral load, activation markers, and CD4 lymphocyte counts, in HIV-infected persons participating in a trial of preventative therapy for tuberculosis. Groups for comparison would be those with incident tuberculosis and those without, stratified according to treatment status. Because preventative therapy is known to be effective, such studies are unlikely to be repeated. A third approach would involve laboratory and clinical follow-up of HIV-infected persons successfully treated for tuberculosis, but at high risk of recurrence, with comparisons between persons suffering recurrences and those who do not. This would allow the distinction between relapse and re-infection, if strains of M. tuberculosis are stored and characterized by restriction fragment length polymorphism [91].
In conclusion, despite the biological evidence of an adverse interaction, epidemiological evidence is less clear concerning the effect of tuberculosis on the progression of HIV disease. Although HIV-infected patients with tuberculosis have a high mortality rate, it is not certain that this results from the effect of tuberculosis itself on immune progression, and there is no evidence that progression of immune deficiency is influenced by tuberculosis prevention, nor that the immunological or virological effects associated with tuberculosis are specific to this infection. Nevertheless, the rates of co-infection with HIV and M. tuberculosis are highest in countries where antiretroviral drugs are largely unavailable, and few interventions would benefit the health of HIV-infected people internationally more than the effective control of tuberculosis, the commonest AIDS indicator disease world-wide.
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