Failures of 1 week on, 1 week off antiretroviral therapies in a randomized trial

BACKGROUND: Scheduled treatment interruptions are being evaluated in an effort to decrease costs and side effects of highly active antiretroviral therapy (HAART). A schedule of 1 week on and 1 week off therapy offers the promise of 50% less drug exposure with continuously undetectable HIV RNA concentration. METHODS: In the Staccato study 600 patients on successful HAART were to be randomized to either continued therapy, CD4-guided therapy, or one week on, one week off therapy. A scheduled preliminary analysis evaluated effectiveness in the 1-week-on-1-week-off arm. RESULTS: Of 36 evaluable patients, 19 (53%) had two successive HIV RNA concentrations > 500 copies/ml at the end of the week off therapy, and were classified as virological failure. Most of those who failed took didanosine, stavudine, saquinavir, and ritonavir (11 patients). In these patients, there was no evidence of mutations suggestive of drug resistance, and plasma saquinavir levels were within the expected range. Two of three patients failing on triple nucleotides had drug resistance mutations, but nonetheless responded to reintroduction of triple nucleotide therapy. One of two patients taking nevirapine, and one of eight taking efavirenz, also failed. Both had resistance mutations at the time of failure, but not at baseline. CONCLUSIONS: The 1-week-on-1-week-off schedule, as tested in the Staccato study, showed an unacceptably high failure rate and was therefore terminated.     

Cigarette smoking and its relation to pulmonary tuberculosis in adults

The purpose of this hospital-based case-control study is to determine the effect of passive and active smoking on pulmonary TB in adults. The study subjects were 100 new pulmonary TB cases diagnosed at TB Division, and age-sex matched 100 non-TB cases from patients admitted to Taksin Hospital and healthy subjects who came for annual physical check-up at either the outpatient clinic of the TB division or Taksin Hospital, during May 2001 to October 2001. All subjects had blood tests and only persons who were HIV-negative, DM-negative and free of other lung diseases were included. Data were collected by direct interview using questionnaires. Multivariate analysis of cigarette smoking related to pulmonary TB in adults was performed. The factors related to pulmonary TB in adults were current active smoking regardless of passive smoking exposure. There was a significant association between early age at initiation of smoking and TB. Active (current + ex-active) smokers who started smoking at age 15-20 years had a higher risk of pulmonary TB compared to others (OR = 3.18, 95% CI = 1.15-8.77); as well as the long duration of smoking: persons who had smoked >10 years had a higher risk of pulmonary TB (OR = 2.96, 95% CI = 1.06-8.22). There was a relationship between pulmonary TB and the amount of smoking exposure. Those who smoked >10 cigarettes/day (OR = 3.98, 95% CI = 1.26-12.60) or >3 days/week (OR = 2.68, 95% CI = 1.01-7.09) had higher risk of pulmonary TB compared to non-smokers. Passive smokers who were exposed to tobacco smoke >3 times/week outside the home had a higher risk of pulmonary TB than those with exposure < or =3 times/week (OR = 3.13, 95% CI = 1.07-9.17). It was also found that the effects of passive smoking in the office and/or neighborhood were strong. Persons with such exposures had a higher risk of pulmonary TB than no exposure or exposure < or =3 times/week from either or both places (OR = 4.62, 95% CI = 1.68-14.98). Therefore, an effective anti-smoking campaign is expected to have a positive repercussion on TB incidence. Smoking cessation must be considered and promoted by all levels of health care providers.     

Effects of highly active antiretroviral therapy (HAART) on psychomotor performance in children with HIV disease

OBJECTIVE: This study assesses the effects of HAART on psychomotor performance of symptomatic HIV-infected children. It is one of the first studies to look at neurobehavioral functioning in children infected with HIV in resource-limited countries. DESIGN: A longitudinal pilot study of vertically HIV-infected children at the HIV Netherlands Australia Thailand Research Collaboration Center in Bangkok, Thailand. METHODS: A total of 34 children participated in the study of whom 16 had never received antiretroviral (ARV) therapy and were about to start HAART (Newly treated children), 7 did not receive antiretroviral therapy (Untreated children) and 11 had been treated with HAART for more than one year (HAART experienced children). All children were administered 4 psychomotor tasks at baseline and after 4 months. The Newly treated and the Untreated children were also evaluated after 12 months. RESULTS: In general, the children performed similarly on all psychomotor tasks at baseline. After 12 months of HAART, there was a significant increase in CD4% in the Newly treated group. Overall, psychomotor performance did not change at the 4-month evaluation in all groups. At the 12-month evaluation psychomotor performance had deteriorated substantially on all tasks in both the Newly treated and the Untreated children. CONCLUSIONS: There was no significant difference in psychomotor functioning between children newly treated, previously treated and untreated with HAART over the course of one year. Psychomotor performance deteriorated after 12 months of HAART, which provides important indications concerning the lack of benefits of HAART on psychomotor functions in children despite immunologic reconstitution. Further research with larger sample sizes is needed to confirm these findings.     

Expression,genomic structure and mapping of the thymus specific protease prss16: a candidate gene for insulin dependent diabetes mellitus susceptibility

PRSS16 is a serine protease specifically expressed by epithelial cells in the thymic cortex. The human gene is encoded on 6p21.3-p22 where recent linkage analysis has identified an association with insulin dependent diabetes mellitus (IDDM) susceptibility independent of HLA-DR3. To further investigate its potential role in autoimmunity, we characterized the mouse orthologue, Prss16. The genomic structure of Prss16 shows conservation with the human gene in size, number of exons and chromosomal location. Mapping of Prss16 places it on mouse chromosome 13 centromeric of thesatin locus. This region is comparable to the PRSS16 region on human chromosome 6 and has also been linked to quantitative trait locus for IDDM in the nonobese diabetic mouse. Similar to the human gene, Prss16 expression is highly specific in the mouse with expression limited to the cortical thymic epithelium. Notably, embryonic expression coincides with population of the thymic anlage with T-cell precursors and initiation of T-cell development. We also show that NOD and New Zealand Black mice, which have a disrupted thymic architecture and autoimmune phenotype, have lower levels of Prss16 expression compared to C57BL/6 mice. These findings support the role of Prss16 in T-cell development and susceptibility to autoimmunity in the mouse.     

Serodiagnosis of melioidosis by a competitive enzyme-linked immunosorbent assay using a lipopolysaccharide-specific monoclonal antibody

Burkholderia pseudomallei is the causative agent of melioidosis, a severe and potentially fatal infectious disease in humans known to be endemic in Southeast Asia and northern Australia. The infection is also increasingly recognized in various animal species with a potential to spread to humans. With the potential as a biological warfare agent, specific serodiagnosis of melioidosis for surveillance in large populations at risk, humans or animals, would be highly valuable. In this study, a competitive enzyme-linked immunosorbent assay (ELISA) using a lipopolysaccharide-specific monoclonal antibody was developed. The assay provides high specificity, based on a previously described monoclonal antibody to a specific epitope on the lipopolysaccharide (LPS) of B. pseudomallei. The assay sensitivity of 96.0% and specificity of 100% were achieved at a cutoff value of 50% inhibition in human culture-proven melioidosis cases. An optimal cutoff value of 65% inhibition for sera from a melioidosis endemic area was obtained by ROC analysis and resulted in an assay specificity of 86.2%, while maintaining assay sensitivity of 92.0%. A potential application of the assay in the serodiagnosis of melioidosis in animal species was also evaluated usina dolphin sera with satisfactory results.     

Clusters of Drug-Resistant Mycobacterium tuberculosis Detected by Whole-Genome Sequence Analysis of Nationwide Sample,Thailand, 2014–2017

Multidrug-resistant tuberculosis (MDR TB), pre-extensively drug-resistant tuberculosis (pre-XDR TB), and extensively drug-resistant tuberculosis (XDR TB) complicate disease control. We analyzed whole-genome sequence data for 579 phenotypically drug-resistant M. tuberculosis isolates (28% of available MDR/pre-XDR and all culturable XDR TB isolates collected in Thailand during 2014–2017). Most isolates were from lineage 2 (n = 482; 83.2%). Cluster analysis revealed that 281/579 isolates (48.5%) formed 89 clusters, including 205 MDR TB, 46 pre-XDR TB, 19 XDR TB, and 11 poly–drug-resistant TB isolates based on genotypic drug resistance. Members of most clusters had the same subset of drug resistance-associated mutations, supporting potential primary resistance in MDR TB (n = 176/205; 85.9%), pre-XDR TB (n = 29/46; 63.0%), and XDR TB (n = 14/19; 73.7%). Thirteen major clades were significantly associated with geography (p<0.001). Clusters of clonal origin contribute greatly to the high prevalence of drug-resistant TB in Thailand.     

Restriction fragment length polymorphism study of nationwide samples of Mycobacterium tuberculosis in Thailand, 1997-1998.

SETTING: During 1997-1998, a national anti-tuberculosis drug resistance survey was conducted in Thailand as a part of a global project. OBJECTIVE: To evaluate the IS6110 hybridisation patterns and the level of clustering, which was expected to be low due to the short duration of the sample collection. DESIGN: Eight hundred and twenty-eight bacterial isolates were available for fingerprinting by standard IS6110 hybridisation. RESULTS: The restriction fragment length polymorphism patterns varied with geographic locations, ages of the patients, and resistance to rifampicin and streptomycin. The Beijing strain was more common among younger patients, and their prevalence appeared to decrease with the distance from Bangkok, while the opposite was true for the single-banded isolates. Excluding isolates containing five or less copies of IS6110, 26.4% were clustered. Clustering was more common among females. The clustered isolates were sometimes from different provinces and, if resistant to drugs, usually possessed different resistance profiles. CONCLUSIONS: The results question the validity of inferring recent transmission from the clustering of IS6110 hybridisation patterns in some settings in Thailand. The level of recent transmission in a nationwide study in a country with a high incidence of tuberculosis should be evaluated with caution.