By L. Beth Gadkowski*, MD, MS
Jason E. Stout**, MD, MHS

*Disclosures:
Nothing to disclose

**Disclosures:
Nothing to disclose

Tuberculosis (TB) continues to disproportionately afflict persons incarcerated in correctional facilities in the United States (U.S.). A recent study examining surveillance data for all persons with TB disease reported in the U.S. between 1993 and 2003 found that the rate of TB disease among federal (29.4 cases/100,000) and state (24.2/100,000) prison inmates was markedly higher than the rate among non-inmates (6.7/100,000) (see Literature Review).¹ Over half (53.7%) of the inmates with TB disease were housed in local jails, and compared to non-inmates, they were younger, more likely to be male, US-born and from racial and ethnic minorities. Not surprisingly, inmates more often had a history of excess alcohol use, illicit drug use and homelessness during the year prior to TB diagnosis. Co-infection with human immunodeficiency virus (HIV) was common among inmates with TB disease. Among males between the ages of 18 and 64, 25% of the incarcerated were known to be HIV-infected compared to 18% for non-inmates. Further, despite a higher rate of directly observed therapy among inmates than non-inmates, treatment completion rates tended to be worse among inmates than non-inmates, particularly among those who were HIV-infected.

As most prisoners with TB are eventually released, failure to complete treatment in this population poses a significant risk not only to the individual health of the patient, but also to the public health of the community. While the study did not examine the reasons for worse TB treatment outcomes among inmates, several factors may have been contributory. The study spanned 1993 to 2003, and during the early part of this period, TB control efforts were simultaneously recovering from the relative neglect of the previous decade and coping with the emerging HIV/AIDS epidemic. Additionally, the authors suggest that the poor inmate outcomes observed may be the product of fragmentation of care in correctional settings due to inmate transfer between institutions and release from incarceration, which challenge coordinated care to ensure treatment completion. Certainly, socioeconomic factors associated with incarceration may have posed a barrier to healthcare as those who are incarcerated may have less access to care and/or under-utilize care.

Local jails have been particularly implicated in TB transmission, and TB control has been challenging in this setting. A study of TB cases in Maricopa County, Arizona, published in 2005, demonstrated the challenges of TB control in jails.² Of 300 TB cases reported in the county from 1999 to 2000, 73 (24%) occurred in persons who had a history of incarceration in the county jail. Similar to national statistics, TB patients with a history of incarceration had higher rates of homelessness and substance abuse than other TB patients. The TB patients in the study who had been in the county jail were incarcerated a total of 370 times, but spent a median of only two days in jail each time they were incarcerated. This short length of stay and the requirement of at least 48 hours to place and read a tuberculin skin test (TST) may explain why 83% of inmates had no record of tuberculin skin testing in jail. Innovative strategies for screening (e.g. Quantiferon-Gold®, see below) and enhanced follow-up after incarceration are needed to target this high-risk population.

Occupational Hazard of TB Infection among Healthcare Workers in Prisons and Jails
TB is an occupational hazard for healthcare professionals who work in correctional settings. Past studies have demonstrated a relatively high incidence of latent TB infection (LTBI) in correctional healthcare workers,³ with infection rates estimated to be as high as 6.6%.⁴ However, a recent study of correctional healthcare workers suggested that a significant proportion of LTBI may be acquired outside the workplace.⁵ The study authors surveyed correctional healthcare professionals in Rhode Island, Maryland and Texas. Tuberculin skin testing practices varied by site, and two-step testing (i.e. repeat tuberculin skin testing one to three weeks following an initial negative TST result) was generally not used. The prevalence of LTBI was 18%, with an estimated infection rate of 1.3%/year. The risk of TB infection correlated with birth in a high-incidence country, but not with job title, duration of employment or TB screening practices in the workplace.

The results of this study reinforce the importance of TB screening among correctional healthcare staff at the time of hire and the use of the two-step testing procedure to distinguish prior TB infection from infection acquired in the workplace Persons with remote TB infection may have a negative TST on initial testing, but placement of the TST stimulates the immune system, which may cause the next TST to be positive in a previously infected person. If the next TST is placed one to three weeks later, it is unlikely that a new exposure to TB has occurred; a positive TST likely represents a boosting of the immune response and not new infection. If two-step testing is not performed, a positive TST during screening the following year will be interpreted as recent TB infection when in fact it may represent immune boosting. Continued refinement of TB surveillance strategies will be necessary to accurately detect ongoing TB transmission in the high-risk correctional environment.

To assist in protecting healthcare workers, in December 2005 Centers for Disease Control and Prevention (CDC) released "Guidelines for Preventing the Transmission of Mycobacterium tuberculosis in Health-Care Settings, 2005."⁶ The document divides healthcare facilities into low risk, medium risk and potential ongoing transmission settings, based on the number of patients with TB disease seen at the facility. The recommended frequency of healthcare worker TST screening varies depending on the facility risk level. Correctional healthcare facilities are classified as medium risk unless ongoing TB transmission is identified and all correctional healthcare facilities should have a written TB infection control plan.

In medium risk settings, all healthcare workers should receive baseline TB screening upon hire (either with two-step tuberculin skin testing or a single interferon-g release assay, e.g. QuantiFERON®). After baseline testing, healthcare workers should receive TB screening annually, including screening for symptoms and either tuberculin skin testing or interferon-g release assay for persons with previously negative tests. Healthcare workers with a positive baseline test, a newly positive test or documentation of previous treatment for latent or TB disease should receive one chest radiograph to exclude TB disease. Yearly chest radiographs are not needed unless TB symptoms are present. In the setting of ongoing transmission within a facility, TB testing may need to be performed as frequently as every eight to 10 weeks until there is no further evidence of TB transmission.

Of course, any healthcare worker with LTBI (positive TST or interferon-g release assay, no evidence of active TB disease) should be offered treatment to reduce the risk of future TB disease (See this month's Case Study 1). Tuberculin skin testing should generally not be performed in individuals with a history of a strong positive result in the past. Severe reactions can be triggered with repeat skin testing in such persons.

TB in the HIV-Infected Inmate
HIV co-infection continues to be a significant challenge in treatment of persons with TB. A recent study of 367 patients with HIV/TB co-infection treated in six cities across the U.S. highlighted the difficulties encountered in treating patients with both infections.⁷ Patients had been diagnosed with TB between 1986 and 2000, with 17% diagnosed in 1997 or later - a period during which potent antiretroviral therapies became available. Intolerance of TB drugs was common; 16% of patients required a change in TB treatment regimen due to drug intolerance (see this month's Case Study 2). Drug interactions were another common problem; 73% were concurrently prescribed rifamycins (rifampin, rifabutin) and HIV medications known to interact with rifamycins. Treatment was also complicated by poor adherence and concurrent liver disease. Poor adherence to TB therapy was noted in 38% of cases, and liver disease was present either prior to or during TB treatment in 25% of patients with HIV/TB co-infection. Only 62% of patients completed TB treatment and 17% of patients with HIV/TB co-infection died within 12 months of TB diagnosis.

Fortunately, understanding of pharmacokinetic interactions among drugs used to treat TB and HIV continues to improve. (Updated guidelines for concurrent HIV/TB treatment are available at www.hivatis.org. This month's IDCR-o-GRAM lists major interactions between TB and HIV therapies.) In general, the nucleoside reverse transcriptase inhibitors (NRTIs) only have minor interactions with TB drugs, and no dosing adjustments of either TB or HIV medications are necessary when using HIV regimens containing only nucleoside agents. Serum concentrations of all the available non-nucleoside (NNRTI) agents (delaviridine, efavirenz and nevirapine) are reduced by concurrent rifampin administration, and among these agents, only efavirenz is currently recommended for use in patients receiving rifampin.

A major concern has been the dosing of rifabutin with efavirenz, as both induce cytochrome P450 enzymes. A recent study provided empiric support for the recommendation to increase rifabutin dosing for TB treatment in combination with efavirenz-based regimens. The Tuberculosis Trials Consortium studied 15 patients who received standard doses of isoniazid plus rifabutin dosed 600 mg twice-weekly during the continuation phase (the last four months) of TB treatment.⁸ These patients also received standard-dose efavirenz (600 mg daily) plus two NRTIs for HIV treatment. The increased rifabutin dose was adequate to compensate for efavirenz-induced increases in drug metabolism; the therapy was generally well tolerated and had potent antiretroviral activity.

Concurrent use of protease inhibitors with rifampin is no longer recommended. Although pharmacokinetic data suggested that saquinavir/ritonavir would be effective in combination with rifampin. In a recent report, the combination of saquinavir/ritonavir and rifampin was associated with 11 cases of significant transaminase elevation among 28 healthy volunteers receiving this combination, including one case that required hospitalization.⁹ The saquinavir/ ritonavir combination is, therefore, no longer recommended for use with rifampin. Rifabutin is the preferred rifamycin for patients taking protease inhibitors, and the dosages of rifabutin, the protease inhibitor, or both must be adjusted to compensate for the two-way interaction. (See this month's IDCR-o-GRAM.)

Treatment of patients with HIV/TB co-infection with potent antiretroviral therapies has led to increasing recognition of another complication: immune reconstitution inflammatory syndrome (IRIS). IRIS, defined as clinical deterioration associated with restoration of pathogen-specific immune responses, has been associated with a variety of pathogens including cytomegalovirus, hepatitis B and C, Pneumocystis jiroveci (formerly Pneumocystis carinii), Cryptococcus neoformans and many others. IRIS occurs in 19% to 36% of patients with HIV/TB co-infection who receive both antituberculous and antiretroviral therapy.^10,11 A recent review of IRIS associated with mycobacterial infections identified 86 published cases of HIV/TB-associated IRIS.¹² IRIS occurred in patients with low nadir CD4 counts (median 51 cells/mm³) and was associated with treatment-related significant increases in CD4 counts and decreases in plasma HIV RNA. However, HIV/TB-associated IRIS has been reported in patients with baseline CD4 counts as high as 435.

Extrapulmonary TB and starting antiretroviral therapy prior to completion of two months of TB treatment have also been associated with increased risk for IRIS. In contrast to IRIS associated with pathogens such as M. avium, most persons with HIV/TB-associated IRIS were receiving antituberculous therapy at the time of IRIS onset. Patients typically presented with fever, lymphadenopathy and worsening respiratory symptoms between two to 10 weeks after starting antiretroviral therapy. Lymphadenopathy, which could be peripheral (cervical, supraclavicular, inguinal, axillary) or intrathoracic, was present in 71% of cases. Worsening pulmonary disease, sometimes leading to respiratory failure, occurred in 28% of cases. Antiretroviral therapy was interrupted because of IRIS in 15% of cases, and 7% required surgery to treat IRIS-induced symptoms. Although some manifestations were life-threatening, no deaths due to IRIS were reported. Optimal treatment of IRIS is unclear, but 26% of patients received corticosteroids in an attempt to diminish the exuberant immune response. Recognition of IRIS and perhaps delaying antiretroviral therapy in patients with HIV/TB co-infection who do not have an urgent indication for antiretroviral treatment may reduce morbidity from this condition.

Fluoroquinolones for TB Treatment
Current guidelines recommend the use of isoniazid, rifampin, ethambutol and pyrazinamide as first-line drugs for TB treatment.13 While the rate of multi-drug resistant tuberculosis (MDR-TB), defined as resistance to at least isoniazid and rifampin, is low in the U.S., many patients have difficulty tolerating one or more of the first-line antituberculous agents.¹⁴ However, many of the available second-line agents are poorly tolerated and less effective than the first-line drugs. The fluoroquinolones, therefore, are increasingly promising agents for TB treatment. In fact, one of the most important predictors of successful treatment of MDR-TB is whether the TB isolate demonstrates in vitro susceptibility to a fluoroquinolone.¹⁵

A recent systematic review examined 10 randomized trials that either substituted or added fluoroquinolones to the treatment regimen for pulmonary TB.¹⁶ Older quinolones, like ciprofloxacin and ofloxacin, were associated with a higher incidence of relapse and a longer time to sputum culture conversion when substituted for one or more first-line drugs (ofloxacin instead of rifampin in one study, ciprofloxacin instead of pyrazinamide plus ethambutol in another) in patients with TB disease sensitive to all of the first-line drugs. No difference in any significant outcome was found comparing a standard four drug regimen to four drugs plus a newer fluoroquinolone, levofloxacin, for the first two months of treatment in a patient population suspected to have high rates of drug-resistant TB. Other trials in drug-resistant TB compared fluoroquinolones (levofloxacin vs. ofloxacin and sparfloxacin vs. ofloxacin) that were either substituted or added to drug regimens. In these studies, the fluoroquinolone used did not make a significant difference with regard to cure rate or treatment failure. Importantly, regimens including fluoroquinolones were not associated with an increase in adverse events over standard regimens.

In contrast, more impressive results were reported from a recent study that substituted moxifloxacin for ethambutol during the first eight weeks of pulmonary TB treatment in sputum smear-positive patients.¹⁷ A preliminary analysis of 301 patients enrolled in this study prior to January 2005 demonstrated that patients receiving moxifloxacin converted their sputum cultures to negative earlier than patients receiving ethambutol (median 43 days for moxifloxacin vs. 56 days for ethambutol, p=0.01). Moxifloxacin was generally well-tolerated: fever, nausea and dizziness were commonly reported, but seldom resulted in treatment discontinuation. These results suggest that moxifloxacin is a useful second-line agent for TB treatment, and studies are underway to examine its utility as a first-line agent.

Alternative TB Test
The Mantoux TST in which 0.1 ml of tuberculin purified protein derivative is injected into the inner surface of the forearm, is the accepted method of evaluating for TB or LTBI. However, this test may be falsely reactive in individuals who have received the Bacille Calmette-Guèrin (BCG) vaccine. The usefulness of TST is also limited by the inherent variability in its administration and interpretation. QuantiFERON-TB Gold® (QFT-G) was approved by the Food and Drug Administration (FDA) in December 2004 as a diagnostic test for active TB and LTBI. The test measures the release of interferon-gamma (IFN-gamma) when whole blood is incubated with peptides found in M. tuberculosis. These peptides, early secretory antigenic target-6 (ESAT-6) and culture filtrate protein-10 (CFP-10), are secreted from M. tuberculosis and pathogenic M. bovis strains, but are not found in BCG or nontuberculous mycobacteria except M. kansasii, M. szulgai and M. marinum. As a result, QFT-G results are not affected by previous BCG vaccination or environmental exposure to nontuberculous mycobacteria. This test takes the place of the first-generation QuantiFERON® test, which is no longer being marketed.

The QFT-G test has the same logistical issues as the first generation test. Blood drawn for the test needs to be incubated less than 12 hours after being collected and lab personnel require special training to perform the assay. However, QFT-G results are available in less than 24 hours and unlike the TST, only one clinic visit is required. This makes QFT-G an attractive testing option in clinical settings such as homeless shelters and jails where follow-up can be challenging. QFT-G is also potentially a cost-effective alternative to TST testing in institutions like correctional facilities and health care settings where false positive tests can prompt additional costly testing.

The CDC released guidelines for use of QFT-G in December 2005 (see Resources).¹⁸ According to these guidelines, QFT-G may be used in all circumstances in which the TST is currently used, including contact investigations, targeted TST of high-risk groups such as immigrants, surveillance screening (such as in healthcare workers or correctional facilities), or as an aid to diagnosis of TB disease. However, there is a paucity of data to support the use of the test among immunocompromised persons (e.g. HIV-infected, those on chronic corticosteroids, recipients of tumor necrosis factor-alpha inhibitors, etc.) or in children. Furthermore, while the QFT-G is likely more specific than the TST for LTBI, it may be less sensitive than the TST for detection of LTBI. Use of QFT-G instead of the TST in the correctional setting, particularly in the setting of a significant foreign-born incarcerated population, seems attractive, but careful attention should be paid to quality assurance and impact on correctional system healthcare costs.

Conclusions
Despite continued decline in TB in the U.S. as a whole, TB will continue to be a significant problem within the correctional system. Available data indicate that greater attention to the development and implementation of systems is urgently needed to ensure prisoners and former inmates complete TB treatment. Further, continued vigilance and adherence to good infection control policies in prisons and jails will be vital to protecting correctional healthcare workers as well as others in the correctional setting. New diagnostic tools, including blood tests for TB infection, are becoming available to improve TB diagnosis, but much work remains to be done. Shorter and better tolerated regimens are needed for treatment of both latent and active TB. Treatment of persons co-infected with HIV/TB continues to be challenging because of high pill burden, drug interactions and tolerability, but as HIV treatment is simplified, some of these challenges may be overcome. IRIS is another important challenge for HIV/TB co-infected patients, and trials of different treatment strategies to optimize IRIS management, including the sequencing of TB and HIV therapy, are underway. The key to TB control is to improve diagnosis and treatment in countries where TB is highly endemic; only by controlling TB in the rest of the world is there any hope of eliminating TB in the US.

References:
1 MacNeil JR, Lobato MN, Moore M. An unanswered health disparity: tuberculosis among correctional inmates, 1993 through 2003. Am J Public Health. 2005; 95(10):1800-5.
2 MacNeil JR, McRill C, Steinhauser G, et al. Jails, a neglected opportunity for tuberculosis prevention. Am J Prev Med. 2005; 28(2):225-8.
3 Steenland K, Levine AJ, Sieber K, et al. Incidence of tuberculosis infection among New York State prison employees. Am J Public Health. 1997; 87(12):2012-14.
4 Field MJ, Institute of Medicine. Committee on Regulating Occupational Exposure to Tuberculosis. Tuberculosis in the workplace. Washington, D.C: National Academy Press, 2001.
5 Mitchell CS, Gershon RR, Lears MK, et al. Risk of tuberculosis in correctional healthcare workers. J Occup Environ Med. 2005; 47(6):580-6.
6 CDC. Guidelines for preventing the transmission of Mycobacterium tuberculosis in health-care settings, 2005. MMWR. 2005; 54(RR-17):1-141.
7 Dworkin MS, Adams MR, Cohn DL, et al. Factors that complicate the treatment of tuberculosis in HIV-infected patients. J Acquir Immune Defic Syndr. 2005; 39(4):464-70.
8 Weiner M, Benator D, Peloquin CA, et al. Evaluation of the drug interaction between rifabutin and efavirenz in patients with HIV infection and tuberculosis. Clin Infect Dis. 2005; 41(9):1343-9.
9 ACC Editors. Drug-induced hepatitis with saquinavir/ritonavir + rifampin. AIDS Clin Care, 2005; 17(3):32.
10 Narita M, Ashkin D, Hollender ES, et al. Paradoxical worsening of tuberculosis following antiretroviral therapy in patients with AIDS. Am J Respir Crit Care Med. 1998; 158(1):157-61.
11 Burman W, Khan A, Vernon A, et al, Tuberculosis Trials Constortium. Immune reconstitution inflammatory syndrome among patients with HIV-related tuberculosis. 42nd Annual Meeting of the Infectious Diseases Society of America. October 3, 2004. Boston, MA.
12 Lawn SD, Bekker LG, Miller RF. Immune reconstitution disease associated with mycobacterial infections in HIV-infected individuals receiving antiretrovirals. Lancet Infect Dis. 2005; 5(6):361-73.
13 Blumberg HM, Burman WJ, Chaisson RE, et al. American Thoracic Society/Centers for Disease Control and Prevention/Infectious Diseases Society of America: treatment of tuberculosis. Am J Respir Crit Care Med. 2003; 167(4):603-62.
14 Yee D, Valiquette C, Pelletier M, et al. Incidence of serious side effects from first-line antituberculosis drugs among patients treated for active tuberculosis. Am J Respir Crit Care Med. 2003; 167(11):1472-7.
15 Tahaoglu K, Torun T, Sevim T, et al. The treatment of multidrug-resistant tuberculosis in Turkey. N Engl J Med. 2001; 345(3):170-4.
16 Ziganshina LE, Vizel AA, Squire SB. Fluoroquinolones for treating tuberculosis. Cochrane Database Syst Rev 2005;(3):CD004795.
17 Burman W, Tuberculosis Trials Constortium. Results From TBTC Study 27: An Evaluation Of The Activity And Tolerability Of Moxifloxacin During The First Two Months Of Treatment For Pulmonary Tuberculosis. American Thoracic Society 100th Anniversary Meeting, San Diego, CA 2005.
18 Mazurek GH, Jereb J, Lobue P, et al. Guidelines for using the QuantiFERON-TB Gold test for detecting Mycobacterium tuberculosis infection, United States. MMWR. 2005; 54(RR-15):49-55.

Back to Top