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Tuberculosis and Chest Unit, Grantham Hospital
Tuberculosis Service, Department of Health, Hong Kong, China
PATHOGENESIS AND IMMUNITY OF TUBERCULOSIS
Among the reported genomic alterations of Mycobacterium tuberculosis, those involving the phospholipase C gene are of significant interest (1, 2). Talarico and colleagues published an earlier investigation regarding the genetic diversity of four M. tuberculosis phospholipase C–encoding genes (plcA, plcB, plcC, and plcD) as a result of IS6110 insertions and associated deletions among 106 clinical isolates from Turkey (3). Forty (38%) isolates showed interruptions of the plcD gene. The proportions of isolates with interruptions in the plcA, plcB, and plcC were 3.8, 1.9, and 3.8%, respectively. These findings may allude to the likely greater importance of the plcD gene over the other phospholipase C–encoding components.
Yang and coworkers further addressed the relevance of mycobacterial phospholipase C gene D (plcD) mutations in the clinical presentation of tuberculosis by integrating comparative genomics and epidemiologic data analysis (4). Among 496 well-characterized clinical isolates of M. tuberculosis, 147 (30%) were found to have regional interruptions (insertions or insertions + deletions) of the gene. Patients infected with the plcD mutant types were twice as likely to have extrathoracic disease as those infected with the wild types (adjusted odds ratio [OR], 2.19; p = 0.005). Thoracic tuberculosis was defined as disease confined to the lung, pleura, and intrathoracic lymph nodes, whereas patients with extrathoracic disease referred to those who had extrathoracic involvement alone, as well as those with concomitant thoracic disease. When analysis was restricted to 275 isolates with distinct DNA fingerprint patterns, the same association (adjusted OR, 2.74; p = 0.005) was still observed. Further analysis by breakdown of extrathoracic tuberculosis into three categories showed a strong association of plcD mutations with isolated extrathoracic organ involvement (adjusted OR, 3.17; 95% confidence interval [CI], 1.36–7.38), marginal association with disseminated disease (adjusted OR, 1.88; 95% CI, 0.91–3.90), and no association with extrathoracic lymphadenitis (adjusted OR, 1.46; 95% CI, 0.35–6.13). One drawback of the study was the lack of information regarding the HIV status for about half of the patients, but having unknown HIV status was not found to be associated with extrathoracic tuberculosis in multivariate analysis. Thus, the findings of Yang and coworkers suggest that the plcD gene of M. tuberculosis might be potentially involved in the pathogenesis of tuberculosis, with resultant variation in its clinical presentation (4). Although a causal relationship could not be proven, the study is of value in prompting further pursuit of possible gene targets for functional studies in the hope of identifying M. tuberculosis virulence factors.
Granuloma formation and cavitation are key phenomena in the pathogenesis of tuberculosis. The former represents largely a disease containment mechanism, whereas the latter promotes transmission of M. tuberculosis, and perhaps contributes to bacillary persistence. A synthetic matrix metalloproteinase inhibitor was found to promote granuloma formation during the early phase of M. tuberculosis pulmonary infection in a murine model (5). In relation to cavitation, Elkington and coworkers investigated the gene expression of matrix metalloproteinases (MMPs), disintegrin and metalloproteinase families, and tissue inhibitors of metalloproteinases in M. tuberculosis–infected human macrophages by real-time reverse transcriptase–polymerase chain reaction (reverse transcriptase–PCR) (6). Secretion of MMPs was also measured by zymography and Western blotting, and expression in tissue biopsies of patients with pulmonary tuberculosis was localized by immunohistochemistry. Gene expression and secretion of MMP-1 and MMP-7 were shown to be potently up-regulated by M. tuberculosis, with no concomitant increase in tissue inhibitors of metalloproteinases to counteract their activity. Dexamethasone was found to suppress MMP-1, but not MMP-7, gene expression, and secretion. In biopsies taken from patients with tuberculosis, macrophages were shown to express MMP-1 and MMP-7 adjacent to areas of tissue destruction. Thus, the expression and secretion of MMP-1, but not MMP-7, are relatively M. tuberculosis–specific and prostaglandin-dependent. In contrast, the vaccine M. bovis–bacille Calmette Guerin (BCG) was found to increase MMP-7 gene expression and secretion as much as M. tuberculosis, but failed to up-regulate MMP-1. Together with evidence depicting possible association of MMP-1 with pulmonary destruction in other diseases such as emphysema, these data suggest that increased MMP-1 expression in M. tuberculosis–infected macrophages may be a key step in the formation of pulmonary cavities. Modulation of excessive MMP-1 activity may constitute a potential therapeutic target to ameliorate the immunopathology of tuberculosis. The effect of interaction between M. tuberculosis infection and host cytokines on MMP expression may also be a potentially interesting area to pursue further (7).
After the inoculation of M. tuberculosis via aerosolized droplet nuclei, alveolar macrophages and CD4 and CD8 T cells interact in the containment of the microbe and immunopathogenesis of tuberculosis. There is general consensus that CD4 T cells are pivotal in protective immunity against M. tuberculosis. CD8+ T cells play an important role as killer cells of M. tuberculosis–infected targets by lysing bacilli-infected macrophages via a Fas-independent granule exocytosis pathway. The Fas–FasL interaction then results in the apoptotic death of the M. tuberculosis–infected target cells. Human peripheral CD8+ T cells show M. tuberculosis specificity and recognize mycobacterial antigens, such as early secretory antigenic target 6-KDa (ESAT-6), and contribute to production of IFN- and tumor necrosis factor on stimulation with M. tuberculosis.
Carranza and coworkers studied M. tuberculosis growth control by alveolar macrophages and autologous blood CD4+ and CD8+ T cells in healthy household contacts and healthy unexposed community control subjects (8). It was found that CD8+ T cells from healthy household contacts significantly increased control of bacillary growth by autologous alveolar macrophages. In unexposed community contacts, no detectable contribution of CD8+ T cells to growth control was observed. Also, in neither of the two studied groups were CD4+ T cells found to increase bacillary growth control. However, there was no correlation between IFN- and nitric oxide concentrations and growth control of M. tuberculosis conferred by alveolar macrophages and CD8+ T cells. Thus, it is possible that circulating M. tuberculosis–specific CD8+ effector T cells of the host may become expanded systemically after bacillary exposure, and that recruitment of these M. tuberculosis–specific CD8+ T cells from the blood to the local sites of inflammation in the lungs may play an important role in control of the initial infection. These findings might provide useful insights relevant to the development of vaccines and other immunotherapeutic strategies.
Roy and coworkers demonstrated that treatment of M. tuberculosis–infected mice with a single cycle of high-dose intravenous immunoglobulin resulted in substantially reduced bacillary loads in the spleen and lungs (9). Immunoglobulin had no inhibitory effect on the growth of M. tuberculosis in murine bone marrow–derived macrophages. However, analysis of T cells infiltrating the lungs revealed small increases in CD8+ but not CD4+ T-cell numbers in high-dose intravenous immunoglobulin-treated mice.
Irwin and coworkers conducted a study to track antigen-specific CD8+ T cells in the lungs of mice immunized with the tuberculosis vaccine candidate Mtb72F (10). They showed that CD8+ T cells recognizing an immunodominant Mtb32-specific epitope could be detected in significant numbers over the course of infection in mice exposed to low-dose aerosol challenge with M. tuberculosis and that prior vaccination substantially increased the number of these cells at early time points in the lungs. Effector cells were demonstrated by the secretion of IFN-, and very few of them contained granzyme B. However, as the infection progressed, many activated CD8+ T cells down-regulated expression of CD45RB and up-regulated expression of the interleukin-7 (IL-7) receptor chain, indicating their transition to a memory state. These findings support the hypothesis that M. tuberculosis–specific CD8+ T cells can be targeted by vaccination with the Mtb72F polyprotein.
It is becoming increasingly apparent that some additional mechanism is involved in protective immunity against tuberculosis aside from the elaboration of the helper T cell type 1 (Th1) cytokines like IL-12, IFN-, and tumor necrosis factor . It appears that immunity mediated by the Th1 response would only be effective in the absence of another subversive or corrupting influence like a Th2 response involving IL-4 (11). The tenuous understanding of the role of IL-4 production in tuberculosis stemmed from inability of earlier studies to distinguish between the agonist IL-4 and its splice variant IL-42, resulting in data that were difficult to interpret. Dheda and coworkers have recently performed pertinent in vivo and in vitro studies of IL-42 in pulmonary tuberculosis (12). Their objective was to evaluate the levels of messenger RNA (mRNA) encoding IL-4 and IL-42 and their relationship to clinical and treatment parameters in cells from lung lavage and blood of patients with pulmonary tuberculosis. IL-42, IL-4, IFN-, and soluble CD30 levels were measured by PCR and relevant immunoassays in 29 patients with tuberculosis and matched control subjects lacking responses to M. tuberculosis–specific antigens. Levels of mRNA for IL-4 and IL-42 were found to be elevated in unstimulated cells from bronchoalveolar lavage and blood of patients with tuberculosis versus those of the control subjects (p < 0.005). In control subjects, there were low basal levels of IL-4 and IL-42 mRNA expressed mainly by non–T cells (p < 0.05). In patients, there were higher levels of mRNA for both cytokines in the T-cell and non–T-cell populations. Radiologic extent of disease also correlated with the IL-4/IFN- ratio and soluble CD30 level (p < 0.005). After antituberculosis chemotherapy, IL-4 mRNA levels remained unchanged, whereas IL-42 levels increased in parallel with IFN- (p < 0.05). Sonicates of M. tuberculosis were found to up-regulate expression of IL-4 relative to IL-42 in mononuclear cell cultures from patients (p < 0.05). Thus, an immunologic response driven by M. tuberculosis antigens, and involving both IL-4 and IL-42, is likely to be important in the pathogenesis of tuberculosis. Thus, IL-4/IL-42 ratio, a variable that may be altered by treatment, is a possible marker of disease activity.
Rook and coworkers have also reviewed the relevance of these findings in relation to tuberculosis vaccine development (13). They suggested that geographic variation in the efficacy of BCG might be related to presence of a cross-reactive background Th2-like response (probably attributable to exposure of mother and infant to helminthes and environmental mycobacteria) that stops M. tuberculosis from being pushed into a latent state by a protective Th1 response. Thus, a successful vaccine, rather than concentrating solely on the Th1 response, might need to suppress the preexisting subversive Th2-like component as well.
Other means of addressing the Th1 and Th2 balance were also explored by investigators worldwide. For example, Silva and coworkers have recently demonstrated that immunotherapy with plasmid DNA encoding the Mycobacterium leprae 65-kD heat-shock protein in association with antituberculosis chemotherapy could provide a more rapid and efficient form of treatment for murine tuberculosis (14). This adjunctive immunomodulation may have a potential role in shortening the duration of chemotherapy.
EPIDEMIOLOGY OF TUBERCULOSIS
The Stop TB Department of the World Health Organization has recently projected that reduction of tuberculosis incidence, prevalence, and deaths can be achieved by 2015 in most parts of the world, but the challenge will be greatest in Africa and Eastern Europe (15).
A number of important articles in 2005 addressed the problem of tuberculosis, largely regarding its epidemiology, in Africa. Three were published in the AJRCCM (16–18). One article focused on the risk of reinfection disease (16). The second article explored the risk of tuberculosis among HIV-infected subjects receiving highly active antiretroviral therapy in sub-Saharan Africa where both infections are common (17). The third article addressed mixed infection by more than one strain of M. tuberculosis in a single host in the same region (18). Each study has potentially significant implications regarding control of tuberculosis in Africa. The findings may possibly be extrapolated to other areas with high tuberculosis prevalence and exuberant HIV infection.
Verver and coworkers demonstrated that the age-adjusted incidence rate of tuberculosis attributable to reinfection after successful treatment could be four times that of new tuberculosis in an area with high prevalence of disease, such as South Africa (16). This observation implies that individuals who had tuberculosis once are at an increased risk of developing the disease again when reinfected. This apparently novel concept deserves attention, as it appears to be contradictory to what would be assumed. However, a few caveats must be borne in mind when interpreting the findings of this important epidemiologic study. Among these are the absence of data regarding the socioeconomic condition and HIV status of the study patients, and the low percentage of available DNA fingerprints from sputum cultures, as well as the substantial proportion of solitary positive cultures from sputum specimens (19, 20). Nevertheless, the message derived from this study merits further exploration, especially in relation to case finding and preventive therapy of the at-risk population in tuberculosis control programs (16). Furthermore, the findings may also underline the need for an accurate distinction between disease due to relapse and reinfection during the follow-up of patients enrolled into antituberculosis chemotherapy trials in areas of high disease prevalence.
In sub-Saharan Africa, tuberculosis remains the top cause of HIV-related mortality. The incidence of tuberculosis in adults receiving highly active antiretroviral therapy (HAART) is lower than in untreated HIV-infected adults, but still higher than among HIV-negative adults (21). Seyler and coworkers performed an analysis on the risk factors for active tuberculosis among HIV-infected subjects receiving HAART in that region (17). They studied a 7-yr prospective cohort of HIV-infected adults, with standardized procedures for documenting morbidity. Included in the analysis were the incidence of active tuberculosis in patients who were started on HAART, as well as the association between baseline patient characteristics and the occurrence of disease. Altogether, 129 adults (with median baseline CD4 count of 125/mm3) were started on HAART and then followed up for 270 person-years. At initiation of HAART, 31 patients had a past history of tuberculosis, but none had currently active disease. During their follow-up assessment, the incidence of active tuberculosis was 4.8/100 person-years overall, 3.0/100 person-years in patients with no tuberculosis history, and 11.3/100 person-years in patients with a history of tuberculosis (adjusted hazard ratio, 4.6; p = 0.02). Thus, the risk of tuberculosis after HAART initiation was found to be significantly higher in patients with a past history of tuberculosis than in those without. This finding, if confirmed by other investigators, might prompt consideration of possible time-limited secondary chemoprophylaxis in sub-Saharan African adults with a past history of tuberculosis during the initiation of HAART.
Conventionally, infection followed by disease is usually attributed to a single strain of M. tuberculosis. The development of DNA fingerprinting has enabled differentiation of M. tuberculosis strains and made possible the documentation of reinfection versus relapse. Evidence of mixed infection by multiple strains in a single host has also been observed (22, 23). van Rie and coworkers recently investigated the changing M. tuberculosis drug-resistance patterns caused by reinfection and mixed infection (18). Serial sputum cultures from 48 patients diagnosed with multidrug-resistant (MDR) tuberculosis were evaluated by phenotypic drug-susceptibility testing and genotypic mutation detection methods. The latter analysis was performed by IS6110 DNA fingerprinting and a novel strain-specific PCR amplification method. DNA fingerprint analysis of serial sputum cultures from these study patients showed that 10 cases were due to reinfection and one case to mixed infection. In contrast, strain-specific PCR amplification in nine cases demonstrated mixed infection in five cases, reinfection in three cases, and laboratory contamination in the remaining case. Correlation with clinical data (especially treatment regimens and timing) suggested that first-line antituberculosis therapy could select for a drug-resistant subpopulation, whereas poor adherence or use of second-line (reserve) drugs could result in the reemergence of the drug-susceptible subpopulations. Thus, van Rie and coworkers have shown that mixed infection might be an important mechanism responsible for observations attributed to reinfection by DNA fingerprinting, and that drug treatment and varying adherence might lead to selective appearance of the dominant mycobacterial subpopulations. The inability to accurately determine resistance patterns in cases of mixed infection might result in inadvertent delays in diagnosis of drug-resistant tuberculosis, which could have undesirable consequences for patient management and control of disease transmission.
Glynn and coworkers recently published an article recapitulating the importance of recent infection with M. tuberculosis in an area with high HIV prevalence, namely northern Malawi in Africa (24). The proportion of strains found to be clustered was among the highest in the world (with a maximum reaching about two-thirds). The association with HIV infection in older adults (adjusted OR, 5.1) may suggest that HIV infection has a greater impact on disease caused by recent transmission than on that caused by reactivation.
The impact of HIV infection on tuberculosis is further exemplified by a recent retrospective cohort study in South African gold miners. Sonnenberg and coworkers analyzed 740 subjects (25). The incidence of tuberculosis increased with time since seroconversion, calendar period, and age. It was 2.90 cases per 100 person-years in HIV-positive miners, and 0.80 cases per 100 person-years in HIV-negative miners (adjusted rate ratio, 2.9). Tuberculosis incidence doubled within the first year of HIV infection (adjusted rate ratio, 2.1). These investigators concluded that the increase in risk of tuberculosis so soon after infection with HIV was unexpected, and current predictive models of tuberculosis incidence could have underestimated the effect of HIV infection in areas where tuberculosis is endemic.
Although tuberculosis preventive therapy could reduce disease incidence among HIV-infected individuals in clinical trials, data on its effectiveness under routine settings were lacking. Grant and coworkers recently published their isoniazid preventive therapy study on 1,655 HIV-infected male employees of a South African gold-mining company recruited from 1999 through 2001 (before the availability of antiretroviral therapy) (26). They found that isoniazid preventive therapy could reduce tuberculosis incidence by 38% overall and by 46% among individuals with no prior history of tuberculosis. Although the data are encouraging, more work is still required to explore new strategies for such therapy.
Aside from HIV coinfection, den Boon and coworkers have recently reported the association between smoking and tuberculosis infection by means of a population survey in South Africa (27). They found a significantly higher positivity rate of tuberculin skin test (TST) among ever-smokers than never-smokers (unadjusted OR, 1.99). A dose–response relationship was also observed, with the highest risk found among those having smoked more than 15 pack-years (adjusted OR, 1.90).
DIAGNOSIS OF TUBERCULOSIS INFECTION
A number of studies have been published recently regarding the utility of IFN- release tests in the diagnosis of tuberculosis infection. In the absence of a gold standard for tuberculosis infection, prudence is warranted in drawing any firm conclusion regarding the performance of the tests. However, these studies still contribute to a better understanding of a difficult issue, and may pave the way for adoption of these tests in routine clinical practices in the near future.
Recent studies have indicated that the new IFN- blood tests might improve specificity and sensitivity in the diagnosis of latent tuberculosis infection as compared with the conventional TST (28). The QuantiFeron-TB Gold (QFT-Gold; Cellestis Ltd., Victoria, Australia) has demonstrated promising results in selected groups of study subjects (28, 29). However, it was unclear whether this test would perform well in an unselected patient population independently evaluated for possible tuberculosis infection. Thus, Ferrara and coworkers attempted to use the QFT-Gold test for diagnosis of tuberculosis infection in the routine hospital setting (30). Their main objective was to evaluate the test in unselected patients for its agreement with the TST; discordant results were interpreted in light of the final clinical diagnosis and potential confounding factors. Of 318 patients tested, 68 (21.4%) gave indeterminate test results, with significant overrepresentation among patients having negative TST (28.9%) as compared with those with positive TST (6.6%). These QFT-Gold indeterminate results also occurred more frequently among patients receiving immunosuppressive therapy than in those who were not (OR, 3.35; p < 0.0001). After exclusion of indeterminate results, the concordance between QFT-Gold and TST was significantly lower in BCG-vaccinated than in nonvaccinated individuals (41.5 vs. 80.3%, p < 0.0001). Furthermore, among 11 patients with active tuberculosis (five culture-positive), QFT-Gold yielded more positive results than TST (66.7 vs. 33.3%, p = 0.165). Ferrara and coworkers concluded that the QFT-Gold test was feasible for routine hospital use in diagnosing tuberculosis infection (30). However, as with TST, immunosuppression might negatively impact the test's performance by resulting in a significant rate of indeterminate results in this most vulnerable patient population. Indeterminate results with this IFN- assay in immunosuppressed subjects may alert the clinician regarding possible anergy, and help to avoid the confusion between anergy and a true negative test result. In this context, the clinician can promptly continue with further investigations to diagnose or exclude tuberculosis in these at-risk patients (31).
Ravn and coworkers have recently published a report regarding the potential value of the Quantiferon-TB RD1 (QFT-RD1) test, using M. tuberculosis–specific antigens, in the diagnosis of active tuberculosis (32). The sensitivity of QFT-RD1 was 85%, and it was higher than that of microscopy (42%, p = 0.001) and culture (59%, p = 0.009). Despite its good sensitivity among patients with active tuberculosis, including those with negative microscopy and culture, the QFT-RD1 remains basically a test for tuberculosis infection rather than disease itself. A positive result is difficult to interpret in areas with a high background prevalence of latent tuberculosis infection.
Pai and coworkers have recently published their experience regarding the assessment of latent tuberculosis infection among health care workers in rural India by whole-blood IFN- assay and TST (33). Among 726 health care workers (68% with direct contact with tuberculosis and 71% with BCG scars), 50% were positive by either TST or IFN- assay, and 31% were positive by both tests. Agreement between the tests was high (81%, = 0.61). Increasing age and years in the health profession were found to be significant risk factors for positive results with both tests. BCG vaccination, as indicated by the presence of a BCG scar, had little impact on the results. Thus, a substantial rate of latent tuberculosis infection was found among health care workers in this developing country with high disease prevalence. Although TST and IFN- assay gave comparable positive rates in this population, substantial differences still remain in their performance and operational characteristics. The decision to choose one test or the other will also depend on the population, purpose of testing, and availability of resources.
The Food and Drug Administration has approved the QFT-Gold test, and is evaluating the enzyme-linked immunospot (ELISPOT) assay, which has already been approved in Europe. The latter test detects individual cytokine-producing T cells. The ELISPOT protocol has now been simplified using automated cell separation vacutainers, and is marketed as the T SPOT-TB test (Oxford Immunotec, Oxford, UK).
Shams and coworkers conducted a study to compare the ELISPOT and TST for detecting latent tuberculosis infection in contacts of patients with tuberculosis (34). Because of the absence of a gold standard for latent tuberculosis infection, the sensitivity and specificity of ELISPOT and TST could not be directly measured. The investigators thus estimated the likelihood of having latent tuberculosis infection by using a contact score that quantified exposure to and infectiousness of the index case, and analyzed the relationship of the contact score to ELISPOT and TST results. The likelihood of a positive ELISPOT (p = 0.0005) and a TST (p = 0.01) increased significantly with rising contact scores. The contact score was more strongly related to the ELISPOT than to the TST results, although the difference was not statistically significant, possibly because of the limited sample size. (An earlier report in the United Kingdom [35] probably achieved this purpose better because of a bigger sample size, but might also have underestimated the sensitivity of the TST.) Foreign-born, BCG-vaccinated persons were significantly more likely to have positive TST than positive ELISPOT (p < 0.0001). Thus, the ELISPOT appears to be at least as sensitive as the TST for diagnosis of latent tuberculosis infection in contacts of patients with tuberculosis, and likely to be more specific than the TST in BCG-vaccinated subjects. This improved specificity corroborates the results of a study conducted in an endemic tropical setting (36). Such an advantage is of potential value in reducing the number of false-positive diagnoses, thus saving unwarranted treatment with cost and toxicity implications.
A recently published study in Korea with intermediate tuberculosis burden has also shown that whole-blood IFN- assay is a better indicator of the risk of M. tuberculosis infection than the TST in a BCG-vaccinated population (37). This study addressed the discrepancy between the two tests for diagnosis of latent tuberculosis infection among four groups of participants with different risks of infection—namely, recent casual contacts, recent close contacts, bacteriologically or pathologically confirmed patients with tuberculosis, and those without identifiable risk of tuberculosis infection.
A study of children with the clinical diagnosis of tuberculosis has shown a detectable response to M. tuberculosis–specific antigens, ESAT-6, or culture filtrate protein 10 (CFP-10) in 70% of the subjects and more frequently in those with culture-proven disease (38). Thus, M. tuberculosis–specific ELISPOT testing is likely a promising tool for diagnosis of tuberculosis in children, as its interpretation is less likely affected by the lower background prevalence of latent tuberculosis infection in this age group. Another study has further shown that use of combined peptide spot counts and fusion protein of ESAT-6/CFP-10 could improve the sensitivity of testing for optimal diagnosis of latent tuberculosis infection (39).
A recent study from Gambia also examined quantitative purified protein derivative (PPD) skin test and PPD ELISPOT results in healthy household contacts of index patients with smear-/culture-positive tuberculosis (40). Both the PPD skin test reaction size and PPD ELISPOT count were more likely to be larger in subjects showing a positive ELISPOT response to a fusion peptide containing ESAT-6/CFP-10 than those not showing this response (p < 0.0001). However, when quantitative PPD skin test and PPD ELISPOT results were compared in ESAT-6–/CFP-10–positive subjects, only the ELISPOT count was sensitive to the exposure gradient. The number of positive spots increased significantly with exposure (p = 0.009), thus implicating its potential value in reflecting the infectious load in recent exposure.
One recent report has also provided preliminary evidence that the ELISPOT test could perform well in diagnosing tuberculosis infection among HIV-positive subjects, including those with low CD4 T-lymphocyte count (41), corroborating the findings of an earlier study in HIV-infected children (42).
TREATMENT OF TUBERCULOSIS
Earlier clinical trials showed that rifapentine (RPE), when given at 600 mg once weekly, led to higher relapse rates of tuberculosis than administration of thrice-weekly or twice-weekly rifampin (RMP) (43, 44). Furthermore, in HIV-positive subjects, monoresistance to rifamycin could emerge when these patients relapsed after RPE treatment (45). Thus, Sirgel and coworkers subsequently conducted a study to compare the early bactericidal activity (EBA) of RPE and its pharmacokinetics with those of RMP, trying to delineate the underlying mechanism for poor clinical response, and mycobacterial regrowth between doses of the rifamycin, which might lead to the development of rifamycin monoresistance at relapse (46). The main objective of the investigation was to determine the dose size of RPE that could provide adequate drug exposure to prevent mycobacterial regrowth. EBA studies were performed over the initial 5 d of treatment in 123 patients with newly diagnosed, previously untreated, and strongly smear-positive pulmonary tuberculosis from two cities in South Africa. The patients were randomly allocated to treatment groups to receive one of the following: (1) RPE 300 mg as a single dose, (2) RPE 600 mg as a single dose, (3) RPE 900 mg as a single dose, (4) RPE 1,200 mg as a single dose, (5) RMP 150 mg for five daily doses, (6) RMP 300 mg for five daily doses, or (7) RMP 600 mg for five daily doses. The EBA was calculated as the fall in log10 cfu/ml of sputum/d. A pharmacokinetic study was also performed on 58 patients (in one city) by measuring time to peak serum concentration, peak serum concentration, and area under concentration–time curve (AUC) for each dose size of the rifamycins and their desacetyl metabolites. It was found that the EBAs for both rifamycins were quite similar: a linear relationship to log dose at lower doses and a curvilinear response at higher doses, with a likely plateau at 1,136 mg for RPE. The ratios of AUC to minimum inhibitory concentration were in agreement for both rifamycins on the assumption that only the fraction of free or non–protein-bound drugs (2% of RPE and 14% of RMP) were pharmacologically active in the lesions. From consideration of the drug pulse size and duration of the postantibiotic lag, a 1,200-mg dose of RPE appeared necessary to improve response and to prevent regrowth between doses of this long-acting cyclopentyl-substituted rifamycin, and hence development of rifamycin monoresistance whether or not an accompanying drug is present. These findings might have potentially significant therapeutic implications.
Although the hypothesis of Sirgel and colleagues is interesting and intriguing, it would be difficult to assume that measures of EBA can adequately guide the dosing of a rifamycin that has a predominant effect on dormant bacilli or persisters (47). Thus, it appears that validated surrogate markers are urgently needed to assess the sterilizing potential of drugs currently in use or under development.
RMP has well-documented interaction with some highly active antiretroviral agents, especially HIV protease inhibitors. An alternate member of the rifamycin class, rifabutin, has much less effect due to its lower enzyme inducing activity on the cytochrome P450 family. Thus, rifabutin-based therapy appears to be a better choice for treatment of HIV-tuberculosis. Burman and coworkers, as well as the Tuberculosis Trials Consortium, prospectively evaluated patients with culture-positive tuberculosis treated in a directly observed setting with 2 mo of rifabutin, isoniazid, pyrazinamide, and ethambutol (given daily, thrice weekly, or twice weekly) followed by 4 mo of twice-weekly rifabutin plus isoniazid (48). Most patients had advanced HIV disease. Nine (5.3%) patients had an adverse outcome of treatment failure or relapse. Eight of the nine (89%) patients had M. tuberculosis isolates with acquired rifamycin resistance. This event was associated with low CD4 lymphocyte count (< 100/mm3). Thus, it appears that intermittent rifabutin-based therapy for HIV-related tuberculosis, while well tolerated, could be associated with a high risk of failure or relapse in the presence of significant immunosuppression.
A study undertaken in New York City furnished findings that corroborate those of Burman and coworkers. HIV-infected patients treated with a RMP-based regimen alone were found to have a higher risk of relapse and acquired RMP resistance if intermittent dosing of RMP was started during the intensive phase of treatment (hazard ratios: 6.7 for relapse, 6.4 for acquired RMP resistance, as compared with those not on intermittent dosing) (49). This association remained when the analysis was confined to patients with CD4 cell counts of less than 100 cu/mm. Thus, it appears that the risk for acquired rifamycin resistance among HIV-infected persons with tuberculosis depends not so much on the rifamycin used but rather on the rifamycin dosing schedule in the intensive phase of treatment.
Weiner and coworkers have recently shown that in patients with HIV and tuberculosis, after adjustment for CD4+ T-cell count, the mean rifabutin drug exposure was significantly lower in those with failure or relapse associated with acquired rifamycin- resistant mycobacteria (ARR failure or relapse) than those without (50). The median isoniazid drug exposure was not significantly associated with ARR failure or relapse. However, in a multivariate logistic regression model that adjusted for rifabutin drug exposure, a lower isoniazid drug exposure was also associated with ARR failure or relapse. Thus, Weiner and coinvestigators concluded that lower plasma concentrations of rifabutin, and perhaps isoniazid, were associated with ARR failure or relapse in patients with tuberculosis and HIV infection treated with twice-weekly antituberculosis therapy.
Ethambutol is a key agent in multidrug regimens used for treatment of Mycobacterium avium complex lung disease. Ocular toxicity is potentially the most important adverse reaction related to ethambutol administration, especially in the elderly population. In a retrospective analysis by Griffith and coworkers (51) of patients enrolled in six prospective treatment protocols for M. avium complex lung disease that included ethambutol, 50 patients (22%) were known to have preexisting ocular disease. While receiving ethambutol, 42% of patients consulted an ophthalmologist, and 10% stopped ethambutol, at least temporarily. Of the patients included in this study, 8 of 139 (6%) on daily therapy were diagnosed with ethambutol-related ocular toxicity, whereas 0 of 90 (0%) on intermittent therapy had any problem (p = 0.05). All patients with such ocular toxicity developed symptoms between outpatient clinic appointments; none were diagnosed with routine visual acuity and color vision testing. All patients returned to baseline ocular status after discontinuation of ethambutol. There are potential limitations of this study in the evaluation of ethambutol ocular toxicity (51). First, visual examination was not performed routinely, and second, there is generally no single diagnostic test that can be performed alone to confirm or exclude ethambutol toxicity.
In another prospective study by Goyal and colleagues, the patients were examined on a monthly basis (52). The visual parameters studied were best-corrected visual acuity, papillary reactions, optic disc changes, color vision, contrast sensitivity, pupil cycle time, visual field charting, and visual evoked potential. Ethambutol-induced toxicity was also seen in 10% of patients. The maximum visual recovery occurred in the first 6 to 8 weeks after stopping ethambutol. Visual recovery was complete in only one patient, but it was partial in the other two patients. In an earlier analysis from Great Britain, 8 out of 10 patients with ocular toxicity were picked up as a result of routine eye examinations at follow-up appointments and only two of these patients were symptomatic (53). Thus, it still appears appropriate to monitor visual acuity and color discrimination during the course of ethambutol therapy. Intermittent therapy with ethambutol appears safer than daily therapy in terms of ocular toxicity and this merits further evaluation (51).
A number of important animal studies focused on the exploration of new regimens that include RPE and/or moxifloxcin. RPE, a long-acting cyclopentyl rifamycin, is currently used together with isoniazid during once-weekly continuation treatment for pulmonary tuberculosis (43, 44). However, HIV-positive patients and those with cavitary disease have higher rates of treatment failure or relapse (54). The former group of patients is also particularly at risk of development of acquired rifamycin monoresistance (45). Moreover, once-weekly isoniazid and RPE have been shown to be less active than thrice- or twice-weekly therapy with RMP and isoniazid (43, 44). Increase of the once-weekly dose of RPE from 10 to 15 mg/kg can significantly improve the pharmacokinetic parameters of the drug. Moxifloxacin, an 8-methoxy fluoroquinolone with a long half-life and potent bactericidal and good sterilizing activities, has been shown to reduce the time to culture conversion in murine tuberculosis (55), as well as producing a stable cure (without relapse) in the same animal model (56).
In a murine model of tuberculosis, Rosenthal and coworkers have recently shown that the sterilizing activity of once-weekly moxifloxacin plus RPE (15 mg/kg) was significantly greater than that of the twice-weekly Denver regimen of isoniazid plus RMP (57). No significant difference in sterilizing effect was demonstrated between once-weekly isoniazid plus RPE (15 mg/kg) and the Denver regimen. These findings are potentially useful in the design of clinical trials on moxifloxacin- and RPE-containing regimens for possible shortening and enhancement of the current antituberculosis treatment regimens. These preliminary data suggest that the efficacy of the once-weekly isoniazid plus RPE continuation treatment can be increased by substituting moxifloxacin for isoniazid, and increasing the dose of RPE to 15 mg/kg. It is encouraging to note that a relatively recent RPE study has shown that serious adverse effects were infrequent even among patients who had higher drug exposures (AUCo-infinity) or peak drug concentrations (58).
Currently, 9-mo daily monotherapy with isoniazid is recommended as first-line treatment for latent tuberculosis infection (59). Alternatively, a 4-mo course of daily RMP has been proposed, but the efficacy of this has largely remained untested (60). A 2-mo course of RMP plus pyrazinamide is no longer recommended for use because of concerns over excessive hepatotoxicity, its efficacy notwithstanding (61).
The priorities for developing better treatment of latent tuberculosis infection would include finding and evaluating regimens (1) that can be administered for a shorter duration and/or at wider intervals and (2) that are effective against MDR M. tuberculosis. Regarding the first goal, RPE, the long-acting rifamycin, has considerable appeal. The current recommendation for empiric therapy of latent tuberculosis infection after exposure to MDR tuberculosis is combination therapy of pyrazinamide with either ethambutol or a fluoroquinolone for 6 to 12 mo, but pertinent clinical data in support of this treatment are lacking.
Nuermberger and coworkers have evaluated several new treatment regimens for latent tuberculosis infection using a previously validated murine model comprising mice immunized with M. bovis BCG to augment host immunity before infection with M. tuberculosis H37Rv (62). The drug regimens used included 3-mo once-weekly RPE-containing regimens and 6-mo moxifloxacin-containing regimens in comparison with isoniazid monotherapy control regimens. Three-month once-weekly regimens of RPE in combination with either isoniazid or moxifloxacin were found to be as active as daily isoniazid for 6 to 9 mo. Six-month daily combinations of moxifloxacin with pyrazinamide, ethionamide, or ethambutol were more active than pyrazinamide plus ethambutol, a regimen recommended for therapy for possible latent tuberculosis infection after exposure to MDR tuberculosis. The combination of moxifloxacin with the experimental nitroimidazopyran PA-824 was especially active. Finally, the Hsp65 DNA vaccine alone had no antituberculosis effect in the murine model, but it was found to augment the mycobactericidal activity of moxifloxacin. These findings, taken together, suggest that RPE, moxifloxacin, and perhaps, therapeutic DNA vaccination might have the potential to improve on current therapy for latent tuberculosis infection.
FOOTNOTES
DOI: 10.1164/rccm.2512002
Conflict of Interest Statement: Neither author has a financial relationship with a commercial entity that has an interest in the subject of this manuscript.
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