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Setting The detection of multidrug-resistant tuberculosis (MDR-TB) using rapid drug susceptibility testing (DST) has increased steadily in recent years in Peru, from 9216 tests in 2010 to 27 021 tests in 2015. Research examining the impact of rapid DST on treatment outcomes is required. Objective To evaluate the association between rapid DST use (nitrate reductase assay, microscopic observation drug susceptibility assay [MODS] and GenoType® MTBDRplus) and treatment outcomes and mortality in MDR-TB patients in Peru. Design Retrospective cohort study of patients diagnosed with pulmonary MDR-TB between 2010 and 2013 (with treatment outcomes up to December 2015) using the electronic registry of the Peruvian National TB Programme. Results A total of 2671 MDR-TB patients were included; the median age was 27 years, 2.8% were co-infected with the human immunodeficiency virus. Use of rapid DST was associated with a 40% increase in the adjusted odds of treatment success (aOR 1.40, 95%CI 1.19-1.64) and a 54% reduction in mortality (aOR 0.46, 95%CI 0.33-0.64). Higher treatment success rates were driven by MODS and GenoType® MTBDRplus testing (aORs for unsuccessful outcomes respectively 0.68 and 0.66). Conclusion The use of rapid DST (MODS and MTBDRplus) to diagnose MDR-TB was associated with a reduction in the odds of death and a substantial increase in the odds of treatment success.

BACKGROUND: In Peru, a treatment approach for extensively drug-resistant tuberculosis (XDR-TB) incorporating World Health Organization Group 5 drugs and patient-centred care has achieved 65% success. To extend this approach to pre-XDR-TB patients, we evaluated this population separately. OBJECTIVE: To assess programmatic management of pre-XDR-TB. METHOD: Retrospective study using the official national registry from 2011 to 2014. Cases were separately evaluated according to resistance to fluoroquinolones (FQs) (pre-XDR-F) or to second-line injectables (SLIs) (pre-XDR-I). RESULTS: Of 610 pre-XDR-TB patients, 120 (20%) had pre-XDR-F and 490 (80%) had pre-XDR-I. Pre-XDR-F cases were older (34 years vs. 28 years, P < 0.001) and a higher proportion had previously received two or more regimens (70% vs. 38%, P < 0.001). Among the 452 patients who started treatment in 2011-2013, treatment success was 43.3%, 26.5% were lost to follow-up, 12.1% died and 13.7% failed treatment. Success was higher in pre-XDR-I (48.5%) than pre-XDR-F (21.4%) patients. History of previous treatment (OR 2.23, 95%CI 1.52-3.38) and pre-XDR-F (OR 2.39, CI 1.18-4.83) were associated with unsuccessful outcomes. CONCLUSION: Programmatic management of pre-XDR-TB has not been successful, particularly in pre-XDR-F patients, with lower rates of success than those achieved in the same setting for XDR-TB. The strategy used for XDR-TB should be extended to pre-XDR-TB patients in Peru.

Genotype F is one of the less-studied genotypes of human hepatitis B virus, although it is widely distributed in regions of Central and South American. Our previous studies have shown that HBV genotype F is prevalent in Chile, and phylogenetic analysis of its full-length sequence amplified from the sera of chronically infected patients identified it as HBV subgenotype F1b. We have previously reported the full-length sequence of a HBV molecular clone obtained from a patient chronically infected with genotype F1b. In this report, we established a system to study HBV replication based on hepatoma cell lines transfected with full-length monomers of the HBV genome. Culture supernatants were analyzed after transfection and found to contain both HBsAg and HBeAg viral antigens. Consistently, fractionated cell extracts revealed the presence of viral replication, with both cytoplasmic and nuclear DNA intermediates. Analysis of HBV-transfected cells by indirect immunofluorescence or immunoelectron microscopy revealed the expression of viral antigens and cytoplasmic viral particles, respectively. To test the functionality of the ongoing viral replication further at the level of chromatinized cccDNA, transfected cells were treated with a histone deacetylase inhibitor, and this resulted in increased viral replication. This correlated with changes posttranslational modifications of histones at viral promoters. Thus, the development of this viral replication system for HBV genotype F will facilitate studies on the regulation of viral replication and the identification of new antiviral drugs.

Background: Meropenem/clavulanate (MC) has been prescribed to treat MDR/XDR-TB cases, although limited scientific evidence exists. Aim: To retrospectively evaluate the effectiveness, safety, and tolerability of MC added to build an optimal regimen when treating MDR/XDR-TB patients. Methods: An observational, retrospective, cohort study was performed in 5 countries across Europe and South America, where consecutive patients with bacteriologically proven MDR-TB were recruited and divided by MC exposure. Information on demographic, epidemiological, microbiological, and clinical variables were collected from the clinical files using standardized e-forms. Results: A cohort of 264 MDR-TB patients was established: 96 patients were treated with MC-containing regimens and 168 without. Only thirteen (5.2%) were HIV-infected. The proportion of XDR-TB was higher in those exposed to MC-containing regimens (49.0% vs. 6.0%), as was the median (IQR) number of antibiotic resistances (8[6-9] vs 5[4-6]). Sputum smear and culture conversion rates were not statistically different in MDR-TB cases exposed and not exposed to MC-containing regimens, including the XDR-TB subgroup (88.0% vs. 100.0%, P=1.00, and 88.0% vs. 100.0%, P=1.00, respectively). Only 6 MC-related adverse events were reported. In 4 cases, MC was re-started after interruption Conclusion: MC-containing regimens can help achieve sputum culture conversion in MDR/XDR-TB cases with no significant toxicity. This study suggests a potential added value of MC in severe forms of drug-resistant TB when an optimal regimen can not be built with available drugs.

Background: Carbapenems are used to treat MDR/XDR-TB cases in order to build a robust regimen, however limited evidence of their effectiveness exists. Aim: To compare the therapeutic contribution of imipenem and amoxicillin/clavulanate (IC) vs. meropenem and amoxicillin/clavulanate (MC) added to background regimens to treat MDR/XDR-TB cases. Methods: An observational, retrospective, cohort study was performed in 5 centres in Europe and South America, consecutive adult patients with bacteriologically proven MDR-TB were recruited and divided by MC and IC exposure. Demographic, epidemiological, microbiological, and clinical variables were collected using standardized e-forms. Results: A cohort of 180 MDR-TB patients were enrolled: 84 and 96 were treated with IC and MC respectively. Both groups had similar median number of antibiotic resistances (8 vs. 8) but more fluoroquinolone resistance (79.0% vs. 48.9% ; p-value: Conclusion: Our study suggests that MC is safe and more effective than IC in treating M/XDR-TB patients.

Tuberculosis (TB) is the first cause of death by an infectious agent in the world, the incidence in the population is declining very slowly and drug resistance is currently considered an international crisis. In Peru, the recent TB Prevention and Control Act in Peru (Law 30287) declares the fight against TB of national interest. In recent years, the Ministry of Health’s (MINSA) National Health Strategy for the Prevention and Control of Tuberculosis (ESNPCT) has achieved significant progress in the control of this disease; however, challenges still remain to be addressed. This article reviews the epidemiological situation of TB in Peru, systematizes the progress achieved during the management of the ESNPCT team between the years 2011 and 2015 from the biomedical approach, public management and social determinants of health, also posing challenges to achieving TB control under law 30287 and the “End of TB” strategy of the World Health Organization (WHO).

Indexación: Web of Science With about 350 million people chronically infected around the world hepatitis B is a major health problem. Template for progeny HBV synthesis is the viral genome, organized as a minichromosome (cccDNA) inside the hepatocyte nucleus. How viral cccDNA gene expression is regulated by its chromatin structure; more importantly, how the modulation of this structure impacts on viral gene expression remains elusive. Here, we found that the enzyme SetDB1 contributes to setting up a repressed cccDNA chromatin state. This repressive state is activated by the histone lysine demethylase-1 (LSD1). Consistently, inhibiting or reducing LSD1 levels led to repression of viral gene expression. This correlates with the transcriptionally repressive mark H3K9 methylation and reduction on the activating marks H3 acetylation and H3K4 methylation on viral promoters. Investigating the importance of viral proteins we found that LSD1 recruitment to viral promoters was dependent on the viral transactivator protein HBx. Moreover, the histone methyltransferase Set1A and HBx are simultaneously bound to the core promoter, and Set1A expression correlates with cccDNA H3K4 methylation. Our results shed light on the mechanisms of HBV regulation mediated by the cccDNA chromatin structure, offering new therapeutic targets to develop drugs for the treatment of chronically infected HBV patients. http://www.nature.com/articles/srep25901