Genetic Diversity of Mycobacterium tuberculosis in Peru and Exploration of Phylogenetic Associations with Drug Resistance

Abstract

BackgroundThere is limited available data on the strain diversity of M tuberculosis in Peru, though there may be interesting lessons to learn from a setting where multidrug resistant TB has emerged as a major problem despite an apparently well-functioning DOTS control programme.MethodsSpoligotyping was undertaken on 794 strains of M tuberculosis collected between 1999 and 2005 from 553 community-based patients and 241 hospital-based HIV co-infected patients with pulmonary tuberculosis in Lima, Peru. Phylogenetic and epidemiologic analyses permitted identification of clusters and exploration of spoligotype associations with drug resistance.ResultsMean patient age was 31.9 years, 63% were male and 30.4% were known to be HIV+. Rifampicin mono-resistance, isoniazid mono-resistance and multidrug resistance (MDR) were identified in 4.7%, 8.7% and 17.3% of strains respectively. Of 794 strains from 794 patients there were 149 different spoligotypes. Of these there were 27 strains (3.4%) with novel, unique orphan spoligotypes. 498 strains (62.7%) were clustered in the nine most common spoligotypes: 16.4% SIT 50 (clade H3), 12.3% SIT 53 (clade T1), 8.3% SIT 33 (LAM3), 7.4% SIT 42 (LAM9), 5.5% SIT 1 (Beijing), 3.9% SIT 47 (H1), 3.0% SIT 222 (clade unknown), 3.0% SIT1355 (LAM), and 2.8% SIT 92 (X3). Amongst HIV-negative community-based TB patients no associations were seen between drug resistance and specific spoligotypes; in contrast HIV-associated MDRTB, but not isoniazid or rifampicin mono-resistance, was associated with SIT42 and SIT53 strains.ConclusionTwo spoligotypes were associated with MDR particularly amongst patients with HIV. The MDR-HIV association was significantly reduced after controlling for SIT42 and SIT53 status; residual confounding may explain the remaining apparent association. These data are suggestive of a prolonged, clonal, hospital-based outbreak of MDR disease amongst HIV patients but do not support a hypothesis of strain-specific propensity for the acquisition of resistance-conferring mutations.

Predominant Mycobacterium tuberculosis Families and High Rates of Recent Transmission among New Cases Are Not Associated with Primary Multidrug Resistance in Lima, Peru

“…With the exception of a study on MDR-TB household contacts, in which LAM was most frequent (41), this predominance of the Haarlem genotype has been observed in all Peruvian studies to date (23)(24)(25)42). Despite heterogeneity in the design and size of those studies, the combined data suggest a trend of increasing prevalence of the Haarlem genotype in Lima in the past decade, with an increase from 23.8% to 35.3% (23,25,41,42).…”

“…Despite heterogeneity in the design and size of those studies, the combined data suggest a trend of increasing prevalence of the Haarlem genotype in Lima in the past decade, with an increase from 23.8% to 35.3% (23,25,41,42). Among a selection of MDR-TB and XDR-TB isolates collected in Peru in 2007 to 2009, the prevalence reached 43.6% (24).…”

“…Epidemiological data on TB in Peru have so far consisted largely of reports of the number of cases detected, demographic data for the cases, and drug susceptibility profiles of M. tuberculosis isolates. Despite the increased number of recent studies on genetic diversity (23)(24)(25), data on the molecular epidemiology of TB in this country are limited; the SpolDB4.0 spoligotyping database includes only 96 Peruvian strains among the 39,609 published entries (26).…”

Bacterial Genome Instability

“…Spoligotyping is based on differences between CRISPR-Cas systems to identify bacterial strains (315). This technique helps investigations of evolution and geographical and/or historical studies (316,317) and permits the identification of microbial populations (318) or the analysis of pathogen outbreaks (319). New spacer repeat units are inserted in 5= extremities of CRISPR arrays, which provide information on recent infections.…”

Análisis genómico comparativo de cepas peruanas de Mycobacterium tuberculosis

“…El primer estudio de la diversidad genética de MTB en el Perú de aislados sensible y drogorresistentes, indica que los genotipos predominantes son: LAM (23,8%), T (23,8%), Haarlem (22,3%) y Beijing (9,3%) (12) . Sheen et al reportan como prevalentes a los linajes Haarlem (28,7%), LAM (28,3%) y T (20,3%) en pacientes con TB y VIH (13) . Investigadores del Instituto Nacional de Salud (INS) de Perú, identificaron que pacientes con TB-XDR presentaron los linajes Haarlem (43,6%), T (27,7%), LAM (16,2%) y Beijing (9,5%) (3) .…”