Carol D. Hamilton

Three months of rifapentine and isoniazid for latent tuberculosis infection

BACKGROUND Treatment of latent Mycobacterium tuberculosis infection is an essential component of tuberculosis control and elimination. The current standard regimen of isoniazid for 9 months is efficacious but is limited by toxicity and low rates of treatment completion. METHODS We conducted an open-label, randomized noninferiority trial comparing 3 months of directly observed once-weekly therapy with rifapentine (900 mg) plus isoniazid (900 mg) (combination-therapy group) with 9 months of self-administered daily isoniazid (300 mg) (isoniazid-only group) in subjects at high risk for tuberculosis. Subjects were enrolled from the United States, Canada, Brazil, and Spain and followed for 33 months. The primary end point was confirmed tuberculosis, and the noninferiority margin was 0.75%. RESULTS In the modified intention-to-treat analysis, tuberculosis developed in 7 of 3986 subjects in the combination-therapy group (cumulative rate, 0.19%) and in 15 of 3745 subjects in the isoniazid-only group (cumulative rate, 0.43%), for a difference of 0.24 percentage points. Rates of treatment completion were 82.1% in the combination-therapy group and 69.0% in the isoniazid-only group (P<0.001). Rates of permanent drug discontinuation owing to an adverse event were 4.9% in the combination-therapy group and 3.7% in the isoniazid-only group (P=0.009). Rates of investigator-assessed drug-related hepatotoxicity were 0.4% and 2.7%, respectively (P<0.001). CONCLUSIONS The use of rifapentine plus isoniazid for 3 months was as effective as 9 months of isoniazid alone in preventing tuberculosis and had a higher treatment-completion rate. Long-term safety monitoring will be important. (Funded by the Centers for Disease Control and Prevention; PREVENT TB ClinicalTrials.gov number, NCT00023452.).

Infectious complications of treatment with biologic agents.

Purpose of reviewThere are three tumor necrosis factor-α inhibitors on the US and European markets today, and uncommon but devastating infectious complications accompany their use. This review describes the most important pathogen-specific infections and their relative frequency. Recent literature is summarized that has helped elucidate the pathophysiologic basis for their occurrence. Finally, evolving sets of recommendations for prevention, diagnosis, and treatment of infectious complications of their use are explored. Recent findingsTuberculosis has continued to be the most common pathogen reported in association with infliximab, and less so with etanercept and adalimumab. Determining treated population case rates depends on having an accurate denominator and reflects the local population’s latent infection rate. The same is true for histoplasmosis. Other pathogens requiring intact cellular immunity for control of latent infection have also been reported. Specific recommendations for preventive therapy are being made, but prospective clinical trials are needed to assess the risk–benefit of any particular approach. SummaryMicroorganisms responsible for the infectious complications associated with anticytokine therapy are generally intracellular pathogens or pathogens that commonly exist in a chronic, latent state and are normally held in check by cell-mediated immunity. Diagnosis requires a high index of suspicion and prompt acquisition of appropriate tissue for microscopic examination and microbiologic culture. Prompt empiric therapy that focuses on the most likely infections is necessary to prevent mortality.

Costs and Cost-effectiveness of Four Treatment Regimens for Latent Tuberculosis Infection

RATIONALE Isoniazid given daily for 9 months is the standard treatment for latent tuberculosis infection (LTBI), but its effectiveness is limited by poor completion rates. Shorter course regimens and regimens using directly observed therapy result in improved adherence but have higher upfront costs. OBJECTIVES To evaluate the costs and cost-effectiveness of regimens for the treatment of LTBI. METHODS We used a computerized Markov model to estimate total societal costs and benefits associated with four regimens for the treatment of LTBI: self-administered isoniazid daily for 9 months, directly observed isoniazid twice-weekly for 9 months, directly observed isoniazid plus rifapentine once weekly for 3 months, and self-administered rifampin daily for 4 months. In the base-case analysis, subjects were assumed to have newly positive tuberculin skin tests after recent exposure to infectious tuberculosis. MEASUREMENTS AND MAIN RESULTS We determined the costs of treatment, quality-adjusted life-years gained, and cases of active tuberculosis prevented. In the base-case analysis, rifampin dominated (less costly with increased benefits) all other regimens except isoniazid plus rifapentine, which was more effective at a cost

Vertical Transmission of Multidrug-Resistant Human Immunodeficiency Virus Type 1 (HIV-1) and Continued Evolution of Drug Resistance in an HIV-1–Infected Infant

48,997 per quality-adjusted life year gained. Isoniazid plus rifapentine dominated all regimens at a relative risk of disease 5.2 times the baseline estimate, or with completion rates less than 34% for isoniazid or 37% for rifampin. Rifampin could be 17% less efficacious than self-administered isoniazid and still be cost-saving compared with this regimen. CONCLUSIONS In our model, rifampin is cost-saving compared with the standard therapy of self-administered isoniazid. Isoniazid plus rifapentine is cost-saving for extremely high-risk patients and is cost-effective for lower-risk patients.

Antiretroviral Therapy Effects on Genetic and Morphologic End Points in Lymphocytes and Sperm of Men with Human Immunodeficiency Virus Infection

To confirm the vertical transmission of multidrug-resistant (MDR) human immunodeficiency virus type 1 (HIV-1) and to assess its impact on further evolution of drug-resistant virus in an infant, proviral DNA amplified from infected peripheral blood mononuclear cell cultures was sequenced to identify reverse transcriptase (RT) and protease (PR) mutations. The infant had proviral DNA with evidence of RT mutations (M41L, L74V, and T215Y) and 3 PR substitutions (K20R, M36I, and V82A). After delivery, the mothers proviral DNA had the same substitutions. Phylogenetic analyses of these HIV-1 RT and PR sequences indicated epidemiological linkage. Plasma drug susceptibility was determined by using a recombinant virus assay. Plasma HIV-1 obtained after the infants birth demonstrated reduced susceptibility to zidovudine and ritonavir. Thus, vertical transmission of MDR HIV-1 was demonstrated in the setting of detectable maternal plasma viremia. Further accumulation of broad MDR in the infants virus to 3 antiretroviral classes occurred, despite postnatal therapy.

Synergistic Pandemics: Confronting the Global HIV and Tuberculosis Epidemics

Many human immunodeficiency virus (HIV)-infected persons receive prolonged treatment with DNA-reactive antiretroviral drugs. A prospective study was conducted of 26 HIV-infected men who provided samples before treatment and at multiple times after beginning treatment, to investigate effects of antiretrovirals on lymphocyte and sperm chromosomes and semen quality. Several antiretroviral regimens, all including a nucleoside component, were used. Lymphocyte metaphase analysis and sperm fluorescence in situ hybridization were used for cytogenetic studies. Semen analyses included conventional parameters (volume, concentration, viability, motility, and morphology). No significant effects on cytogenetic parameters, semen volume, or sperm concentration were detected. However, there were significant improvements in sperm motility for men with study entry CD4 cell counts >200 cells/mm(3), sperm morphology for men with entry CD4 cell counts < or =200 cells/mm(3), and the percentage of viable sperm in both groups. These findings suggest that nucleoside-containing antiretrovirals administered via recommended protocols do not induce chromosomal changes in lymphocytes or sperm but may produce improvements in semen quality.

Therapeutic Drug Monitoring of Antimycobacterial Drugs in Patients with Both Tuberculosis and Advanced Human Immunodeficiency Virus Infection

This supplement was envisioned to summarize the critical issues related to the 2 most deadly infectious diseases worldwide: human immunodeficiency virus (HIV) infection and AIDS and tuberculosis (TB). Together, these infections—1 viral and 1 bacterial, 1 recently emergent and 1 ancient—kill almost 4 million persons every year, most of whom live in developing nations. In tandem, HIV infection and TB create a deadly synergy. TB is the leading cause of death among persons with HIV infection, and areas with a high prevalence of HIV infection have had dramatic increases in the incidence of TB disease. The US government has played a leadership role in addressing the HIV and TB pandemics, most recently through the enactment of the Tom Lantos and Henry J. Hyde United States Global Leadership Against HIV/AIDS, Tuberculosis and Malaria Authorization Act of 2008, which authorized

Extrapulmonary tuberculosis, human immunodeficiency virus, and foreign birth in North Carolina, 1993 – 2006

48 billion over 5 years to combat these deadly infectious diseases in developing nations. We hope that this supplement of scientific review articles focused on HIV infection prevention, TB, and HIV and TB coinfection will serve as a resource for policy makers, HIV and TB program

Extensively drug-resistant tuberculosis: are we learning from history or repeating it?

Study Objective. To determine the feasibility of therapeutic drug monitoring for adjusting low serum antimycobacterial concentrations in patients with both tuberculosis and advanced human immunodeficiency virus (HIV).

Association between 16S-23S internal transcribed spacer sequence groups of Mycobacterium avium complex and pulmonary disease

BackgroundThe proportion of extrapulmonary tuberculosis (EPTB) reported in the United States has been gradually increasing. HIV infection and foreign birth are increasingly associated with tuberculosis and understanding their effect on the clinical presentation of tuberculosis is important.MethodsCase-control study of 6,124 persons with tuberculosis reported to the North Carolina Division of Public health from January 1, 1993 to December 31, 2006. Multivariate logistic regression was used to obtain adjusted odds ratios measuring the associations of foreign birth region and US born race/ethnicity, by HIV status, with EPTB.ResultsAmong all patients with tuberculosis, 1,366 (22.3%) had EPTB, 563 (9.2%) were HIV co-infected, and 1,299 (21.2%) were foreign born. Among HIV negative patients, EPTB was associated with being foreign born (adjusted ORs 1.36 to 5.09, depending on region of birth) and with being US born, Black/African American (OR 1.84; 95% CI 1.42, 2.39). Among HIV infected patients, EPTB was associated with being US born, Black/African American (OR 2.60; 95% CI 1.83, 3.71) and with foreign birth in the Americas (OR 5.12; 95% CI 2.84, 9.23).ConclusionForeign born tuberculosis cases were more likely to have EPTB than US born tuberculosis cases, even in the absence of HIV infection. Increasing proportions of foreign born and HIV-attributable tuberculosis cases in the United States will likely result in a sustained burden of EPTB. Further research is needed to explore why the occurrence and type of EPTB differs by region of birth and whether host genetic and/or bacterial variation can explain these differences in EPTB.