N Engl J Med

Background In regions with high burdens of tuberculosis and human immunodeficiency virus (HIV), many HIV-infected adults begin antiretroviral therapy (ART) when they are already severely immunocompromised. Mortality after ART initiation is high in these patients, and tuberculosis and invasive bacterial diseases are common causes of death. Methods We conducted a 48-week trial of empirical treatment for tuberculosis as compared with treatment guided by testing in HIV-infected adults who had not previously received ART and had CD4+ T-cell counts below 100 cells per cubic millimeter. Patients recruited in Ivory Coast, Uganda, Cambodia, and Vietnam were randomly assigned in a 1:1 ratio to undergo screening (Xpert MTB/RIF test, urinary lipoarabinomannan test, and chest radiography) to determine whether treatment for tuberculosis should be started or to receive systematic empirical treatment with rifampin, isoniazid, ethambutol, and pyrazinamide daily for 2 months, followed by rifampin and isoniazid daily for 4 months. The primary end point was a composite of death from any cause or invasive bacterial disease within 24 weeks (primary analysis) or within 48 weeks after randomization. Results A total of 522 patients in the systematic-treatment group and 525 in the guided-treatment group were included in the analyses. At week 24, the rate of death from any cause or invasive bacterial disease (calculated as the number of first events per 100 patient-years) was 19.4 with systematic treatment and 20.3 with guided treatment (adjusted hazard ratio, 0.95; 95% confidence interval [CI], 0.63 to 1.44). At week 48, the corresponding rates were 12.8 and 13.3 (adjusted hazard ratio, 0.97 [95% CI, 0.67 to 1.40]). At week 24, the probability of tuberculosis was lower with systematic treatment than with guided treatment (3.0% vs. 17.9%; adjusted hazard ratio, 0.15; 95% CI, 0.09 to 0.26), but the probability of grade 3 or 4 drug-related adverse events was higher with systematic treatment (17.4% vs. 7.2%; adjusted hazard ratio 2.57; 95% CI, 1.75 to 3.78). Serious adverse events were more common with systematic treatment. Conclusions Among severely immunosuppressed adults with HIV infection who had not previously received ART, systematic treatment for tuberculosis was not superior to test-guided treatment in reducing the rate of death or invasive bacterial disease over 24 or 48 weeks and was associated with more grade 3 or 4 adverse events

Systematic or test-guided treatment for tuberculosis in HIV-infected adults

A trial involving HIV-infected patients with CD4+ T-cell counts below 100 cells per cubic millimeter compared strategies of systematic treatment for TB and treatment only if testing revealed infection. Systematic treatment was not better than treatment guided by testing with respect to the rate of death or bacterial infection. Background In regions with high burdens of tuberculosis and human immunodeficiency virus (HIV), many HIV-infected adults begin antiretroviral therapy (ART) when they are already severely immunocompromised. Mortality after ART initiation is high in these patients, and tuberculosis and invasive bacterial diseases are common causes of death. Methods We conducted a 48-week trial of empirical treatment for tuberculosis as compared with treatment guided by testing in HIV-infected adults who had not previously received ART and had CD4+ T-cell counts below 100 cells per cubic millimeter.Patients recruited in Ivory Coast, Uganda, Cambodia, and Vietnam were randomly assigned in a 1:1 ratio to undergo screening (Xpert MTB/RIF test, urinary lipoarabinomannan test, and chest radiography) to determine whether treatment for tuberculosis should be started or to receive systematic empirical treatment with rifampin, isoniazid, ethambutol, and pyrazinamide daily for 2 months, followed by rifampin and isoniazid daily for 4 months. The primary end point was a composite of death from any cause or invasive bacterial disease within 24 weeks (primary analysis) or within 48 weeks after randomization. Results A total of 522 patients in the systematic-treatment group and 525 in the guided-treatment group were included in the analyses.At week 24, the rate of death from any cause or invasive bacterial disease (calculated as the number of first events per 100 patient-years) was 19.4 with systematic treatment and 20.3 with guided treatment (adjusted hazard ratio, 0.95; 95% confidence interval [CI], 0.63 to 1.44). At week 48, the corresponding rates were 12.8 and 13.3 (adjusted hazard ratio, 0.97 [95% CI, 0.67 to 1.40]). At week 24, the probability of tuberculosis was lower with systematic treatment than with guided treatment (3.0% vs. 17.9%; adjusted hazard ratio, 0.15; 95% CI, 0.09 to 0.26), but the probability of grade 3 or 4 drug-related adverse events was higher with systematic treatment (17.4% vs. 7.2%; adjusted hazard ratio 2.57; 95% CI, 1.75 to 3.78).Serious adverse events were more common with systematic treatment. Conclusions Among severely immunosuppressed adults with HIV infection who had not previously received ART, systematic treatment for tuberculosis was not superior to test-guided treatment in reducing the rate of death or invasive bacterial disease over 24 or 48 weeks and was associated with more grade 3 or 4 adverse events.(Funded by the Agence Nationale de Recherches sur le Sida et les Hepatites Virales; STATIS ANRS 12290 ClinicalTrials.gov number,.

L1 retrotransposition is a common feature of mammalian hepatocarcinogenesis

The retrotransposon Long Interspersed Element 1 (LINE-1 or L1) is a continuing source of germline and somatic mutagenesis in mammals. Deregulated L1 activity is a hallmark of cancer, and L1 mutagenesis has been described in numerous human malignancies. We previously employed retrotransposon capture sequencing (RC-seq) to analyze hepatocellular carcinoma (HCC) samples from patients infected with hepatitis B or hepatitis C virus and identified L1 variants responsible for activating oncogenic pathways. Here, we have applied RC-seq and whole-genome sequencing (WGS) to an mouse model of hepatic carcinogenesis and demonstrated for the first time that L1 mobilization occurs in murine tumors. In 12 HCC nodules obtained from 10 animals, we validated four somatic L1 insertions by PCR and capillary sequencing, including T subfamily elements, and one G subfamily example. One of the T insertions carried a 3' transduction, allowing us to identify its donor L1 and to demonstrate that this full-length T element retained retrotransposition capacity in cultured cancer cells. Using RC-seq, we also identified eight tumor-specific L1 insertions from 25 HCC patients with a history of alcohol abuse. Finally, we used RC-seq and WGS to identify three tumor-specific L1 insertions among 10 intra-hepatic cholangiocarcinoma (ICC) patients, including one insertion traced to a donor L1 on Chromosome 22 known to be highly active in other cancers. This study reveals L1 mobilization as a common feature of hepatocarcinogenesis in mammals, demonstrating that the phenomenon is not restricted to human viral HCC etiologies and is encountered in murine liver tumors

Endogenous retrotransposition activates oncogenic pathways in hepatocellular carcinoma

LINE-1 (L1) retrotransposons are mobile genetic elements comprising similar to 17% of the human genome. New L1 insertions can profoundly alter gene function and cause disease, though their significance in cancer remains unclear. Here, we applied enhanced retrotransposon capture sequencing (RC-seq) to 19 hepatocellular carcinoma (HCC) genomes and elucidated two archetypal L1-mediated mechanisms enabling tumorigenesis. In the first example, 4/19 (21.1%) donors presented germline retrotransposition events in the tumor suppressor mutated in colorectal cancers (MCC). MCC expression was ablated in each case, enabling oncogenic beta-catenin/Wnt signaling. In the second example, suppression of tumorigenicity 18 (ST18) was activated by a tumor-specific L1 insertion. Experimental assays confirmed that the L1 interrupted a negative feedback loop by blocking ST18 repression of its enhancer. ST18 was also frequently amplified in HCC nodules from Mdr2(-/-) mice, supporting its assignment as a candidate liver oncogene. These proof-of-principle results substantiate L1-mediated retrotransposition as an important etiological factor in HCC