Protease inhibitor-containing antiretroviral treatment and tuberculosis: can rifabutin fill the breach?

OBJECTIVE: To assess how to best manage co-administration of rifabutin (RFB) and human immunodeficiency virus 1 (HIV-1) protease inhibitor (PI) containing antiretroviral treatment (ART). Recommended for initial anti-tuberculosis treatment, rifampicin (RMP) lowers PI concentrations below therapeutic levels, posing significant challenges for ART. As RFB has little effect on PI concentrations, it could be an alternative to RMP. METHODS: A review of the scientific literature on the safety and efficacy of RFB for adult tuberculosis (TB) treatment was conducted, focusing on ART-TB co-therapy. A cost comparison was performed between treatment regimens, and estimates of the burden of TB disease in patients on ART were used to model RFB demand in low- and middle-income countries (LMICs). RESULTS: Eleven clinical studies were identified, comprising 1543 TB patients treated with RFB; 980 (64%) were living with HIV. RFB was as safe and effective as RMP, including in 313 patients receiving co-administered ART (unboosted PIs included indinavir, nelfinavir or saquinavir; a minority received ritonavir [RTV] boosted amprenavir or saquinavir). The total cost for 6 months of all HIV and TB treatment containing RTV-boosted lopinavir (LPV) and RFB is US$410, compared to US$455 if RMP is used with LPV super-boosted with RTV. Our model suggests that demand for RFB in LMICs could be between 10,000 and 18,000 courses by 2012. CONCLUSION: RFB is effective and safe in combination with the PIs studied, cost-saving for co-therapy with currently recommended boosted PIs, and may have a pivotal role in the roll-out of ART. Further research into a daily dose of RFB to simplify dosing regimens and developing fixed-dose combinations can enhance the public sector roll-out of ART.

Acyclovir and transmission of HIV-1 from persons infected with HIV-1 and HSV-2.

BACKGROUND: Most persons who are infected with human immunodeficiency virus type 1 (HIV-1) are also infected with herpes simplex virus type 2 (HSV-2), which is frequently reactivated and is associated with increased plasma and genital levels of HIV-1. Therapy to suppress HSV-2 reduces the frequency of reactivation of HSV-2 as well as HIV-1 levels, suggesting that suppression of HSV-2 may reduce the risk of transmission of HIV-1. METHODS: We conducted a randomized, placebo-controlled trial of suppressive therapy for HSV-2 (acyclovir at a dose of 400 mg orally twice daily) in couples in which only one of the partners was seropositive for HIV-1 (CD4 count, > or = 250 cells per cubic millimeter) and that partner was also infected with HSV-2 and was not taking antiretroviral therapy at the time of enrollment. The primary end point was transmission of HIV-1 to the partner who was not initially infected with HIV-1; linkage of transmissions was assessed by means of genetic sequencing of viruses. RESULTS: A total of 3408 couples were enrolled at 14 sites in Africa. Of the partners who were infected with HIV-1, 68% were women, and the baseline median CD4 count was 462 cells per cubic millimeter. Of 132 HIV-1 seroconversions that occurred after randomization (an incidence of 2.7 per 100 person-years), 84 were linked within couples by viral sequencing: 41 in the acyclovir group and 43 in the placebo group (hazard ratio with acyclovir, 0.92, 95% confidence interval [CI], 0.60 to 1.41; P=0.69). Suppression with acyclovir reduced the mean plasma concentration of HIV-1 by 0.25 log(10) copies per milliliter (95% CI, 0.22 to 0.29; P<0.001) and the occurrence of HSV-2-positive genital ulcers by 73% (risk ratio, 0.27; 95% CI, 0.20 to 0.36; P<0.001). A total of 92% of the partners infected with HIV-1 and 84% of the partners not infected with HIV-1 remained in the study for 24 months. The level of adherence to the dispensed study drug was 96%. No serious adverse events related to acyclovir were observed. CONCLUSIONS: Daily acyclovir therapy did not reduce the risk of transmission of HIV-1, despite a reduction in plasma HIV-1 RNA of 0.25 log(10) copies per milliliter and a 73% reduction in the occurrence of genital ulcers due to HSV-2. (ClinicalTrials.gov number, NCT00194519.)

A network-informed approach to investigating a tuberculosis outbreak: implications for enhancing contact investigations.

BACKGROUND: To elucidate networks of Mycobacterium tuberculosis transmission, it may be appropriate to characterize the types of relationships among tuberculosis (TB) cases and their contacts (with and without latent TB infection) in addition to relying on traditional efforts to distinguish 'close' from 'casual' contacts. SETTING: A TB outbreak in a US low incidence state. OBJECTIVE: To evaluate whether social network analysis can provide insights into transmission settings that might otherwise go unrecognized by routine practices. DESIGN: All adult outbreak-associated cases (n = 19) and a convenience sample of their contacts with and without latent TB infection (LTBI) (n = 26) were re-interviewed in 2001 using a structured questionnaire. Network analysis software was used to create diagrams illustrating important persons within the outbreak network, as well as types of activities TB cases engaged in with their contacts. RESULTS: Drug use and drug sharing were more commonly reported among cases and their infected contacts than among contacts without LTBI. TB cases central to the outbreak network used crack cocaine, uncovering the need to focus control efforts on specific sites and persons involved in illicit drug use. CONCLUSION: Outbreaks occur even in areas with low TB incidence, frequently among groups whose drug use or other illegal activities complicate control efforts. TB programs should consider the use of network analysis as a supplement to routine contact investigations to identify unrecognized patterns of M. tuberculosis transmission.

Extensive transmission of Mycobacterium tuberculosis among congregated, HIV-infected prison inmates in South Carolina, United States.

BACKGROUND: In August 1999, a prison inmate infected with the human immunodeficiency virus (HIV) was diagnosed with pulmonary tuberculosis (TB). This source patient lived in a prison dormitory housing over 300 HIV-infected men, and was symptomatic for at least 2 months prior to diagnosis. We report a large outbreak of TB in HIV-infected prison inmates with subsequent transmission of Mycobacterium tuberculosis outside the prison. METHODS: Exposed inmates were screened by symptom review, chest radiograph and tuberculin skin test (TST) in September and December 1999. We recorded CD4 cell counts, viral loads and receipt of highly active antiretroviral therapy (HAART). RESULTS: The source patient lived on the right side of a two-sided dormitory exclusively housing HIV-infected men. Of 114 men tested from the right side, 75 (66%) had documented TST conversions. Of 96 converters overall, 82 (85%) had TSTs measuring > or = 15 mm. Within 6 months of diagnosis of TB in the source patient, 30 additional inmates and a healthcare worker who cared for the source patient developed TB disease. Two other inmates developed TB disease in spring of 2001. CONCLUSIONS: We describe extensive transmission of M. tuberculosis in a group of HIV-infected prison inmates with high TST conversion rates and subsequent transmission in the community. In settings where HIV-infected persons are congregated, the consequences of TB outbreaks are magnified.

Drug-drug interactions in inmates treated for human immunodeficiency virus and Mycobacterium tuberculosis infection or disease: an institutional tuberculosis outbreak.

The use of rifamycins is limited by drug interactions in human immunodeficiency virus (HIV)-infected persons who are receiving highly active antiretroviral therapy (HAART). During a tuberculosis (TB) outbreak at a prison housing HIV-infected inmates, rifabutin was used to treat 238 men (13 case patients and 225 contacts). Steady-state peak plasma rifabutin concentrations were obtained after rifabutin dosages were adjusted for men receiving single-interacting HAART (with either 1 protease inhibitor [PI] or efavirenz), multi-interacting HAART (with either 2 PIs or > or =1 PI with efavirenz), and for noninteracting HAART (>1 nucleoside reverse-transcriptase inhibitor or no HAART) without rifabutin dose adjustments. Low rifabutin concentrations occurred in 9% of those receiving noninteracting HAART, compared with 19% of those receiving single-interacting and 29% of those receiving multi-interacting HAART (chi2, 3.76; P=.05). Of 225 contacts treated with rifabutin-pyrazinamide, 158 (70%) completed treatment while incarcerated. Rifabutin-pyrazinamide therapy was difficult to implement, because of the need for dosage adjustments and expert clinical management.

An investigation of suspected exogenous reinfection in tuberculosis patients in Kampala, Uganda.

Exogenous reinfection with Mycobacterium tuberculosis is an important phenomenon that occurs with unknown frequency in both immunocompromised and immunocompetent persons. As previous investigations suggest that exogenous reinfection can occur in both of these populations, we reviewed data for 40 cases of suspected TB relapse in an attempt to determine the frequency of this phenomenon in patients treated at the TB Research Unit in Kampala, Uganda. Our findings suggest that while this entity can occur in immunocompetent persons, immunocompromised persons are probably at higher risk for exogenous reinfection with M. tuberculosis.

A preventable outbreak of tuberculosis investigated through an intricate social network.

In 1998, a city in Indiana reported 4-fold increase in the number of cases of tuberculosis (TB). An investigation to assess the increase in cases and to identify possible epidemiologic links among persons with TB identified 41 cases of active TB. Epidemiologic links and/or matching DNA fingerprints were identified for 31 patients (76%). The majority of these patients were members of a single social network within the community. Links for most of these patients were identified after multiple interviews with patients and their contacts. TB control activities in the county were limited prior to the identification of the outbreak. At least 24 cases may have been preventable. This outbreak may have been prevented with prompt case identification and effective contact tracing and screening during the years before the outbreak. The use of social networks should be considered in the investigation of outbreaks that involve difficult-to-reach populations. TB control measures should be maintained in areas with historically low TB incidence.

Outbreak of multidrug-resistant tuberculosis at a methadone treatment program.

SETTING: An out-patient methadone treatment program MTP). OBJECTIVE: To investigate transmission of multidrug-resistant tuberculosis (MDR-TB) in the MTP. DESIGN: Cases were defined as MTP clients or staff who developed TB between 1 January 1994 and 1 January 1996, with at least one positive culture for Mycobacterium tuberculosis resistant to isoniazid and rifampin. Contacts were identified, located and evaluated. RESULTS: Thirteen cases of MDR-TB occurred among 462 clients and staff. One fifth (6/30) of the members of a counseling group for human immunodeficiency virus (HIV) infected clients developed MDR-TB. Individuals known to be HIV positive were at greater risk for TB than those who were HIV negative (RR 5.2, 95%CI 1.2-22.7). Of 449 clients and staff identified as contacts, 393 (87.5%) were located and screened. Among those with a negative baseline tuberculin skin test, 18.5% (56/303) were skin test converters. Attendance at the MTP during a period when the index case was infectious was associated with an increased risk of conversion (RR 2.5, 95%CI 1.1-6.0). CONCLUSION: Extensive transmission of MDR-TB occurred at an out-patient MTP serving numerous clients with HIV infection. This outbreak underscores the importance of developing effective strategies to prevent TB transmission in this setting.

A multi-state outbreak of tuberculosis among members of a highly mobile social network: implications for tuberculosis elimination.

SETTING: Baltimore, Maryland. OBJECTIVE: To describe a tuberculosis (TB) outbreak among a highly mobile population and the efforts required to control it. DESIGN: Epidemiologic outbreak investigation. RESULTS: Between June 1998 and January 2000, 20 TB outbreak cases were identified, of which 18 were culture-confirmed. Seventeen isolates of Mycobacterium tuberculosis had an identical 11-band DNA fingerprint; another isolate had one additional band and was considered a match. Two cases were diagnosed in New York City; another patient lived primarily in Atlanta, but was diagnosed in Baltimore. Persons in the outbreak were predominantly young (median age 24 years), black, male, infected with the human immunodeficiency virus (HIV), and gay, transvestite or transsexual. Activities common among many TB cases included attending two nightclubs, membership in one of three social 'Houses', attending balls or pageants in East Coast cities, marijuana use, and prostitution. Community outreach, extended contact tracing, DNA fingerprinting, directly-observed therapy, and expanded use of preventive therapy were utilized to assess and control the outbreak. During the outbreak period the Baltimore City TB rate declined by 10%. However, additional public health personnel were required to control the outbreak, resulting in a 17% increase in TB clinic staff. CONCLUSION: As TB rates decline, remaining cases are likely to occur in difficult-to-reach populations. Increased resources per case of TB treated will be required to eliminate TB.

Analysis of Mycobacterium tuberculosis transmission patterns in a homeless shelter outbreak.

SETTING: From July 1997 through May 1998, ten tuberculosis (TB) cases were reported among men in a Syracuse New York homeless shelter for men. OBJECTIVE AND DESIGN: Investigation to determine extent of, and prevent further, transmission of Mycobacterium tuberculosis. RESULTS: Epidemiologic and laboratory evidence suggests that eight of the ten cases were related. Seven cases had isolates with matching six-band IS6110 DNA fingerprints; the isolate from another case had a closely related fingerprint pattern and this case was considered to be caused by a variant of the same strain. Isolates from eight cases had identical spoligotypes. The source case had extensive cavitary disease and stayed at the shelter nightly, while symptomatic, for almost 8 months before diagnosis. A contact investigation was conducted among 257 shelter users and staff, 70% of whom had a positive tuberculin skin test, including 21 with documented skin test conversions. CONCLUSIONS: An outbreak of related TB cases in a high-risk setting was confirmed through the use of IS6110 DNA fingerprinting in conjunction with spoligotyping and epidemiologic evidence. Because of the high rate of infection in the homeless population, routine screening for TB and preventive therapy for eligible persons should be considered in shelters.

Extensive transmission of Mycobacterium tuberculosis from a child.

BACKGROUND AND METHODS: Young children rarely transmit tuberculosis. In July 1998, infectious tuberculosis was identified in a nine-year-old boy in North Dakota who was screened because extrapulmonary tuberculosis had been diagnosed in his female guardian. The child, who had come from the Republic of the Marshall Islands in 1996, had bilateral cavitary tuberculosis. Because he was the only known possible source for his female guardian's tuberculosis, an investigation of the child's contacts was undertaken. We identified family, school, day-care, and other social contacts and notified these people of their exposure. We asked the contacts to complete a questionnaire and performed tuberculin skin tests. RESULTS: Of the 276 contacts of the child whom we tested, 56 (20 percent) had a positive tuberculin skin test (induration of at least 10 mm), including 3 of the child's 4 household members, 16 of his 24 classroom contacts, 10 of 32 school-bus riders, and 9 of 61 day-care contacts. A total of 118 persons received preventive therapy, including 56 young children who were prescribed preventive therapy until skin tests performed at least 12 weeks after exposure were negative. The one additional case identified was in the twin brother of the nine-year-old patient. The twin was not considered infectious on the basis of a sputum smear that was negative on microscopical examination. CONCLUSIONS: This investigation showed that a young child can transmit Mycobacterium tuberculosis to a large number of contacts. Children with tuberculosis, especially cavitary or laryngeal tuberculosis, should be considered potentially infectious, and screening of their contacts for infection with M. tuberculosis or active tuberculosis may be required.

Risk factors for rifampin mono-resistant tuberculosis.

Use of rifampin is required for short-course treatment regimens for tuberculosis. Tuberculosis caused by isolates of M. tuberculosis with resistance to rifampin and susceptibility to isoniazid is unusual, but it has been recognized through surveillance. Patients with tuberculosis (cases) with rifampin mono-resistance were compared with HIV-matched controls with tuberculosis caused by a drug-susceptible isolate. A total of 77 cases of rifampin mono-resistant tuberculosis were identified in this multicenter study. Three were determined to be laboratory contaminants, and 10 cases had an epidemiologic link to a case with rifampin mono-resistant tuberculosis, suggesting primary acquisition of rifampin-resistant isolates. Of the remaining 64 cases and 126 controls, there was no difference between cases and controls with regard to age, sex, race, foreign birth, homelessness, or history of incarceration. Cases were more likely to have a history of prior tuberculosis than were controls. Of the 38 cases and 74 controls with HIV infection, there was no difference between cases and controls with regard to age, sex, race, foreign birth, homelessness, history of incarceration, or prior tuberculosis. Cases were more likely to have histories of diarrhea, rifabutin use, or antifungal therapy. Laboratory analysis of available isolates showed that there was no evidence of spread of a single clone of M. tuberculosis. Further studies are needed to identify the causes of the development of rifampin resistance in HIV-infected persons with tuberculosis and to develop strategies to prevent its emergence.

A nosocomial outbreak of multidrug-resistant tuberculosis.

BACKGROUND: An outbreak of seven cases (in six patients and one health care worker, all of whom had AIDS) of multidrug-resistant tuberculosis occurred in a hospital in Chicago. The hospital had a respirator-fit testing program but no acid-fast bacilli isolation rooms. OBJECTIVE: To identify risk factors for transmission of Mycobacterium tuberculosis. DESIGN: Retrospective cohort study. SETTING: Private hospital. PARTICIPANTS: Patients and health care workers exposed to M. tuberculosis. MEASUREMENTS: Analysis of M. tuberculosis isolates, tuberculin skin testing, assessment of exposure, and assessment of participant characteristics. RESULTS: All seven M. tuberculosis isolates had matching DNA fingerprints. Of patients exposed to M. tuberculosis, those who developed tuberculosis had lower CD4+ T-lymphocyte counts (P = 0.02) and were more likely to be ambulatory (P = 0.03) than those who did not. Of 74 exposed health care workers, the 11 (15%) who had conversion on tuberculin skin testing were no more likely than those who did not have conversion to report that they always wore a respirator with a high-efficiency particulate air filter. CONCLUSIONS: Transmission of M. tuberculosis occurred in a hospital that did not have recommended isolation rooms. A respirator-fit testing program did not protect health care workers in this setting.

Nosocomial transmission of human immunodeficiency virus and subsequent transmission of multidrug-resistant tuberculosis in a healthcare worker.

A phlebotomist with nosocomially acquired human immunodeficiency virus infection developed tuberculosis 10 months after exposure to multidrug-resistant Mycobacterium tuberculosis during a nosocomial outbreak. Healthcare workers with immunosuppression are at increased risk of tuberculosis if infected and, if exposed, should be considered for preventive therapy regardless of tuberculin skin-test status.