title: Influence of antituberculosis drug resistance and Mycobacterium tuberculosis lineage on outcome in HIV-associated tuberculous meningitis.
abstract: HIV-associated tuberculous meningitis (TBM) has high mortality. Aside from the devastating impact of multidrug resistance (MDR) on survival, little is understood about the influence of other bacterial factors on outcome. This study examined the influence of Mycobacterium tuberculosis drug resistance, bacterial lineage, and host vaccination status on outcome in patients with HIV-associated TBM. Mycobacterium tuberculosis isolates from the cerebrospinal fluid of 186 patients enrolled in two studies of HIV-associated TBM in Ho Chi Minh City, Vietnam, were tested for resistance to first-line antituberculosis drugs. Lineage genotyping was available for 122 patients. The influence of antituberculosis drug resistance and M. tuberculosis lineage on 9-month mortality was analyzed using Kaplan-Meier survival analysis and Cox multiple regression models. Isoniazid (INH) resistance without rifampin resistance was associated with increased mortality (adjusted hazard ratio [HR], 1.78, 95% confidence interval [CI], 1.18 to 2.66; P = 0.005), and multidrug resistance was uniformly fatal (n = 8/8; adjusted HR, 5.21, 95% CI, 2.38 to 11.42; P < 0.0001). The hazard ratio for INH-resistant cases was greatest during the continuation phase of treatment (after 3 months; HR, 5.05 [95% CI, 2.23 to 11.44]; P = 0.0001). Among drug-susceptible cases, patients infected with the "modern" Beijing lineage strains had lower mortality than patients infected with the "ancient" Indo-Oceanic lineage (HR, 0.29 [95% CI, 0.14 to 0.61]; P = 0.001). Isoniazid resistance, multidrug resistance, and M. tuberculosis lineage are important determinants of mortality in patients with HIV-associated TBM. Interventions which target these factors may help reduce the unacceptably high mortality in patients with TBM.
authors.affiliation: Oxford University Clinical Research Unit Vietnam, Wellcome Trust Major Overseas Programme, Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam.
authors.forename: Dau Quang
authors.initials: DQ
authors.lastname: Tho
authors.forename: M Estée
authors.initials: ME
authors.lastname: Török
authors.forename: Nguyen Thi Bich
authors.initials: NT
authors.lastname: Yen
authors.forename: Nguyen Duc
authors.initials: ND
authors.lastname: Bang
authors.forename: Nguyen Thi Ngoc
authors.initials: NT
authors.lastname: Lan
authors.forename: Vo Sy
authors.initials: VS
authors.lastname: Kiet
authors.forename: Nguyen
authors.initials: N
authors.lastname: van Vinh Chau
authors.forename: Nguyen Huy
authors.initials: NH
authors.lastname: Dung
authors.forename: Jeremy
authors.initials: J
authors.lastname: Day
authors.forename: Jeremy
authors.initials: J
authors.lastname: Farrar
authors.forename: Marcel
authors.initials: M
authors.lastname: Wolbers
authors.forename: Maxine
authors.initials: M
authors.lastname: Caws
mesh_terms: D000328:Adult; D000995:Antitubercular Agents / Q000627:therapeutic use*; D005260:Female; D005838:Genotype; D015658:HIV Infections / Q000188:drug therapy* / Q000235:genetics / Q000382:microbiology / Q000401:mortality; D006801:Humans; D007538:Isoniazid / Q000627:therapeutic use*; D008297:Male; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000472:pathogenicity*; D012293:Rifampin / Q000627:therapeutic use; D014390:Tuberculosis, Meningeal / Q000188:drug therapy* / Q000382:microbiology / Q000401:mortality / Q000821:virology; D018088:Tuberculosis, Multidrug-Resistant / Q000235:genetics; D055815:Young Adult
chemical_list: D000995:Antitubercular Agents; D007538:Isoniazid; D012293:Rifampin