Combination of betulinic acid and EGFR-TKIs exerts synergistic anti-tumor effects against wild-type EGFR NSCLC by inducing autophagy-related cell death via EGFR signaling pathway.

BACKGROUND: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have revolutionized the treatment of lung cancer patients with mutated EGFR. However, the efficacy of EGFR-TKIs in wild-type EGFR tumors has been shown to be marginal. Methods that can sensitize EGFR-TKIs to EGFR wild-type NSCLC remain rare. Hence, we determined whether combination treatment can maximize the therapeutic efficacy of EGFR-TKIs. METHODS: We established a focused drug screening system to investigate candidates for overcoming the intrinsic resistance of wild-type EGFR NSCLC to EGFR-TKIs. Molecular docking assays and western blotting were used to identify the binding mode and blocking effect of the candidate compounds. Proliferation assays, analyses of drug interactions, colony formation assays, flow cytometry and nude mice xenograft models were used to determine the effects and investigate the molecular mechanism of the combination treatment. RESULTS: Betulinic acid (BA) is effective at targeting EGFR and synergizes with EGFR-TKIs (gefitinib and osimertinib) preferentially against wild-type EGFR. BA showed inhibitory activity due to its interaction with the ATP-binding pocket of EGFR and dramatically enhanced the suppressive effects of EGFR-TKIs by blocking EGFR and modulating the EGFR-ATK-mTOR axis. Mechanistic studies revealed that the combination strategy activated EGFR-induced autophagic cell death and that the EGFR-AKT-mTOR signaling pathway was essential for completing autophagy and cell cycle arrest. Activation of the mTOR pathway or blockade of autophagy by specific chemical agents markedly attenuated the effect of cell cycle arrest. In vivo administration of the combination treatment caused marked tumor regression in the A549 xenografts. CONCLUSIONS: BA is a potential wild-type EGFR inhibitor that plays a critical role in sensitizing EGFR-TKI activity. BA combined with an EGFR-TKI effectively suppressed the proliferation and survival of intrinsically resistant lung cancer cells via the inhibition of EGFR as well as the induction of autophagy-related cell death, indicating that BA combined with an EGFR-TKI may be a potential therapeutic strategy for overcoming the primary resistance of wild-type EGFR-positive lung cancers.

Primary drug resistance among HIV-1 patients in Hubei Province in 2020-2022 / 公共卫生与预防医学

Objective To investigate the prevalence of primary drug resistance among HIV-1 patients in Hubei Province from 2020 to 2022, and to provide corresponding basis and data support for HIV antiviral therapy (ART) in Hubei Province. Methods During 2020-2022, plasma samples of HIV-1 infected patients before ART were collected., Patients’ demographic data and baseline laboratory test data were also collected. HIV-1 pol region was amplified by in-house method for sub-type typing and drug-resistant mutation site analysis. Results The pol gene sequence was successfully amplified in 242 of 285 cases, with a success rate of 84.9%. CRF07_BC was the predominant HIV-1 sub-type, accounting for 47.11% (114/242), followed by CRF01_AE, accounting for 25.21% (61/242), sub-type B, accounting for 14.16% (35/242), and CRF55_01B, accounting for 4.13% (10/242). The primary resistance rate was 6.20% (15/242). The mutation site of nucleoside reverse transcriptase inhibitors (NRTIs) was mainly M184V, and the mutation sites of non-nucleoside reverse transcriptase inhibitors (NNRTIs) were mainly E138A/G/EG and V179E. These different mutation sites led to different degrees of drug resistance to 12 drugs. The incidence of drug resistance mutation of CRF55_01B sub-type was significantly higher than that of other sub-types. Conclusion The primary drug resistance rate of HIV-1 infected patients is at a slightly high level in Hubei Province, and close monitoring of primary drug resistance and mutation sites should be strengthened before ART, especially for CRF55_01B sub-type.

Computational drug repositioning for the identification of new agents to sensitize drug-resistant breast tumors across treatments and receptor subtypes.

Introduction: Drug resistance is a major obstacle in cancer treatment and can involve a variety of different factors. Identifying effective therapies for drug resistant tumors is integral for improving patient outcomes. Methods: In this study, we applied a computational drug repositioning approach to identify potential agents to sensitize primary drug resistant breast cancers. We extracted drug resistance profiles from the I-SPY 2 TRIAL, a neoadjuvant trial for early stage breast cancer, by comparing gene expression profiles of responder and non-responder patients stratified into treatments within HR/HER2 receptor subtypes, yielding 17 treatment-subtype pairs. We then used a rank-based pattern-matching strategy to identify compounds in the Connectivity Map, a database of cell line derived drug perturbation profiles, that can reverse these signatures in a breast cancer cell line. We hypothesize that reversing these drug resistance signatures will sensitize tumors to treatment and prolong survival. Results: We found that few individual genes are shared among the drug resistance profiles of different agents. At the pathway level, however, we found enrichment of immune pathways in the responders in 8 treatments within the HR+HER2+, HR+HER2-, and HR-HER2- receptor subtypes. We also found enrichment of estrogen response pathways in the non-responders in 10 treatments primarily within the hormone receptor positive subtypes. Although most of our drug predictions are unique to treatment arms and receptor subtypes, our drug repositioning pipeline identified the estrogen receptor antagonist fulvestrant as a compound that can potentially reverse resistance across 13/17 of the treatments and receptor subtypes including HR+ and triple negative. While fulvestrant showed limited efficacy when tested in a panel of 5 paclitaxel resistant breast cancer cell lines, it did increase drug response in combination with paclitaxel in HCC-1937, a triple negative breast cancer cell line. Conclusion: We applied a computational drug repurposing approach to identify potential agents to sensitize drug resistant breast cancers in the I-SPY 2 TRIAL. We identified fulvestrant as a potential drug hit and showed that it increased response in a paclitaxel-resistant triple negative breast cancer cell line, HCC-1937, when treated in combination with paclitaxel.

Prevalence of Primary Drug Resistance Among Newly Diagnosed HIV-1-Infected Individuals in Hunan Province, China.

At present, research on the prevalence of primary drug resistance (PDR) in Hunan Province is limited. Therefore, we explored the current status of HIV-1 PDR in Hunan to provide a basis for antiretroviral therapy (ART) and a theoretical foundation for prevention and control of the HIV/AIDS epidemic. Three hundred seventy newly diagnosed HIV-1-infected individuals who had not received ART in Hunan province, China, were enrolled in the study. Plasma samples were collected, RNA was extracted, two rounds of gene amplification were carried out with the in-house method, and subtype analysis and drug resistance analysis were carried out with relevant software. We found that the most prevalent subtypes of HIV-1 in Hunan Province are CRF_01AE (126/359, 35.1%) and CRF07_BC (85/359, 23.7%). The PDR rate among newly diagnosed HIV/AIDS patients was 10.0% (36/359). Among them, the drug resistance rates of protease inhibitors, nucleotide reverse transcriptase inhibitors, non-nucleotide reverse transcriptase inhibitors, and integrase inhibitors were 0.3% (1/359), 3.3% (12/359), 8.36% (30/359), and 0.6% (2/359), respectively. The distribution of HIV-1 subtypes in Hunan Province is diverse and complex, and the PDR rate has exceeded the low-level warning line set by the World Health Organization (<5%). Therefore, we should conduct pretreatment drug resistance assays to determine the optimal primary ART so that patients can obtain better antiretroviral treatment outcomes and transmission of drug-resistant strains in the population can be blocked.

Trace the History of HIV and Predict Its Future through Genetic Sequences.

Traditional methods of quantifying epidemic spread are based on surveillance data. The most widely used surveillance data are normally incidence data from case reports and hospital records, which are normally susceptible to human error, and sometimes, they even can be seriously error-prone and incomplete when collected during a destructive epidemic. In this manuscript, we introduce a new method to study the spread of infectious disease. We gave an example of how to use this method to predict the virus spreading using the HIV gene sequences data of China. First, we applied Bayesian inference to gene sequences of two main subtypes of the HIV virus to infer the effective reproduction number (GRe(t)) to trace the history of HIV transmission. Second, a dynamic model was established to forecast the spread of HIV medication resistance in the future and also obtain its effective reproduction number (MRe(t)). Through fitting the two effective reproduction numbers obtained from the two separate ways above, some crucial parameters for the dynamic model were obtained. Simply raising the treatment rate has no impact on lowering the infection rate, according to the dynamics model research, but would instead increase the rate of medication resistance. The negative relationship between the prevalence of HIV and the survivorship of infected individuals following treatment may be to blame for this. Reducing the MSM population's number of sexual partners is a more efficient strategy to reduce transmission per the sensitivity analysis.

Ofloxacin resistance in multibacillary new leprosy cases from Purulia, West Bengal: a threat to effective secondary line treatment for rifampicin-resistant leprosy cases.

OBJECTIVES: Purulia is one of the high-endemic districts for leprosy in West Bengal (the eastern part of India). The annual new case detection rate (ANCDR) of leprosy in West Bengal is 6.04/100000 (DGHS 2019-20). Our earlier report provided evidence of secondary drug resistance in relapse cases of leprosy. The aim of the current study was to observe primary drug resistance patterns for dapsone, rifampicin, and ofloxacin amongst new leprosy patients from Purulia, West Bengal in order to better understand the emergence of primary resistance to these drugs. METHODS: In the present study, slit-skin smear samples were collected from 145 newly diagnosed leprosy cases from The Leprosy Mission (TLM) Purulia hospital between 2017 and 2018. DNA was extracted from these samples and the Mycobacterium leprae genome was analyzed for genes associated with drug resistance by polymerase chain reaction (PCR), followed by Sanger sequencing. Wild-type strain (Thai-53) and mouse footpad-derived drug-resistant strain (Z-4) were used as reference strains. RESULTS: Of 145 cases, 25 cases showed mutations in genes associated with resistance to rifampicin, dapsone, and ofloxacin (as described by the World Health Organization, rpoB, folP, and gyrA, respectively) through Sanger sequencing. Of these 25 cases, 16 cases showed mutations in ofloxacin, two cases showed mutations in combinations of ofloxacin and rifampicin, four cases showed a mutation only in rifampicin, one case showed mutations in combinations of rifampicin and dapsone, and two cases showed mutations only in dapsone. CONCLUSION: Results from this study indicated the emergence of resistance to antileprosy drugs in new cases of leprosy. As ofloxacin is the alternate drug for the treatment of rifampicin-resistant cases, the emergence of new cases with resistance to ofloxacin indicates that ofloxacin-resistant M. leprae strains are actively circulating in this endemic region (i.e., Purulia, West Bengal), posing challenges for the effective treatment of rifampicin-resistant cases.

Proportion and trend of primary resistance among Multidrug resistant Tuberculosis patients in Ethiopia.

Background: Evidence based information on the proportion & trend of primary resistance among multidrug resistance (MDR) TB patients is important for designing effective strategies in the control of the disease. Methods: A retrospective record review of 348 MDR/RR-TB patients treated at All African Leprosy Rehabilitation & Training (ALERT) Center from January 2014- December 2018. Categorical variables were compared using Chi-square/Fisher exact test as appropriate. Trend analysis was done using chi-square & linear regression. Logistic regression analysis was done to determine the factors associated with primary MDR/RR TB. Adjusted Odds Ratio (AOR) with 95% CI and p value < 5% were used to report factors associated. Result: Proportion of primary resistance among MDR/RR TB patients was 25.9% with 95% CI 21.3-30.3%. The proportion increased form 9.7% in 2014 to 43.4% in 2018 at a yearly increasing rate of 9.27%. Contact history to TB patient & year of diagnosis 2017 and 2018 were significantly associated with primary resistance AOR (95% CI) & p value 4.15(1.75-9.84) p = 0.001, 3.87(1.44-10.39) p = 0.007, 3.43(1.20-9.84) p = 0.022 respectively. Conclusion: The study revealed a high proportion of primary resistance among MDR/RR TB during the study period with a linearly increasing fashion thus a need for due attention in the efforts to control MDR TB.

[A real world study on the relationship between drug resistance of targeted therapy and prognosis of HER-2-positive advanced breast cancer].

Objective: To explore the effect of primary and acquired resistance to anti-human epidermal growth factor receptor 2 (HER-2) on the overall survival of patients with HER-2 positive advanced breast cancer. Methods: The clinical characteristics of HER-2 positive patients with advanced breast cancer admitted to Cancer Hospital of Chinese Academy of Medical Sciences from January 1998 to December 2018 were collected, and their neoadjuvant/adjuvant and advanced three-line chemotherapy were summarized. Among them, targeted drugs for HER-2 included trastuzumab, pertuzumab, T-DM1, RC48-ADC, lapatinib, pyrotinib, allitinib, sipatinib, seratinib. Based on the duration of benefit from anti HER-2 treatment, the patients were divided into two groups: primary anti HER-2 resistance group and acquired anti HER-2 resistance group. In this study, the overall survival (OS) was used as the main end point. Kaplan-Meier analysis and Cox proportional risk regression model were used to analyze the effects of different drug resistance mechanisms on the overall survival. Results: The whole group of 284 patients were included. The median age of recurrence and metastasis was 48 years old, 155 (54.6%) were hormone receptor (HR) positive and 129 (45.4%) were HR negative, 128 cases (45.1%) were premenopausal and 156 cases (54.9%) were postmenopausal, 277 cases (97.5%) had a score of 0-1 in ECoG PS and 7 cases (2.5%) had a score of more than 2 in the first diagnosis of relapse and metastasis. There were 103 cases (36.3%) in the primary drug resistance group and 181 cases (63.7%) in the secondary drug resistance group. The median overall survival time of the two groups was 24.9 months and 40.4 months, respectively, with statistical significance (P<0.001). Conclusion: Primary resistance to HER-2 is one of the factors of poor prognosis in HER-2 positive breast cancer, and its mechanism needs to be further explored.

A real world study on the relationship between drug resistance of targeted therapy and prognosis of HER-2-positive advanced breast cancer / 中华肿瘤杂志

Objective: To explore the effect of primary and acquired resistance to anti-human epidermal growth factor receptor 2 (HER-2) on the overall survival of patients with HER-2 positive advanced breast cancer. Methods: The clinical characteristics of HER-2 positive patients with advanced breast cancer admitted to Cancer Hospital of Chinese Academy of Medical Sciences from January 1998 to December 2018 were collected, and their neoadjuvant/adjuvant and advanced three-line chemotherapy were summarized. Among them, targeted drugs for HER-2 included trastuzumab, pertuzumab, T-DM1, RC48-ADC, lapatinib, pyrotinib, allitinib, sipatinib, seratinib. Based on the duration of benefit from anti HER-2 treatment, the patients were divided into two groups: primary anti HER-2 resistance group and acquired anti HER-2 resistance group. In this study, the overall survival (OS) was used as the main end point. Kaplan-Meier analysis and Cox proportional risk regression model were used to analyze the effects of different drug resistance mechanisms on the overall survival. Results: The whole group of 284 patients were included. The median age of recurrence and metastasis was 48 years old, 155 (54.6%) were hormone receptor (HR) positive and 129 (45.4%) were HR negative, 128 cases (45.1%) were premenopausal and 156 cases (54.9%) were postmenopausal, 277 cases (97.5%) had a score of 0-1 in ECoG PS and 7 cases (2.5%) had a score of more than 2 in the first diagnosis of relapse and metastasis. There were 103 cases (36.3%) in the primary drug resistance group and 181 cases (63.7%) in the secondary drug resistance group. The median overall survival time of the two groups was 24.9 months and 40.4 months, respectively, with statistical significance (P<0.001). Conclusion: Primary resistance to HER-2 is one of the factors of poor prognosis in HER-2 positive breast cancer, and its mechanism needs to be further explored.

HIV-1 Drug Resistance Among Treatment-Naive Transgenders from India.

Transgenders (TGs) are highly affected by HIV with high prevalence of 3.14% in India. Since 2017, targeted preventive efforts have been initiated by the government and HIV-infected TGs are being provided the antiretroviral (ART) treatment. Information on the primary HIV drug resistance is crucial for appropriate treatment selection to curb further spread of HIV in this population. In this study, we analyzed HIV-1 pol gene sequences from 36 TGs for presence of drug resistance mutations. To our knowledge, this first study from India reports high-level primary drug resistance (13.8%) among the TG population. Mutations M184V, A98G, K103N, G190A, and Y318F associated with resistance to nucleoside reverse transcriptase inhibitor and non-nucleoside reverse transcriptase inhibitors were observed. All pol gene sequences revealed HIV-1 subtype C in all study TG. High-level HIV-1 drug resistance warrant nationwide larger studies on TGs to understand the level of primary ART drug resistance among this population.

Tumor Extrinsic Factors Mediate Primary T-DM1 Resistance in HER2-Positive Breast Cancer Cells.

To explore if the tumor microenvironment contributes to the primary resistance of HER2-positive breast cancer cells to T-DM1, we examined whether Matrigel, a basement membrane matrix that provides a three-dimensional (3D) cell culture condition, caused the primary resistance of HER2-positive, T-DM1-sensitive breast cancer cells (JIMT1 and SKBR-3 cells) to T-DM1. This is different from the conventional approach such that the cells are exposed with escalated doses of drug to establish a drug-resistant cell line. We found that these cells were able to grow and form spheroids on the Matrigel in the presence of T-DM1. We further explored the molecular mechanisms that enables these cells to be primarily resistant to T-DM1 and found that EGFR was activated in the spheroids, leading to an increased HER2 tyrosine phosphorylation. This in turn enhances cell growth signaling downstream of EGFR/HER2 in the spheroids. HER2 tyrosine phosphorylation promotes receptor internalization and degradation in the spheroids, which limits T-DM1 access to HER2 on the cell surface of spheroids. Blocking EGFR activity by erlotinib reduces HER2 tyrosine phosphorylation and enhances HER2 cell surface expression. This enables T-DM1 to gain access to HER2 on the cell surface, resumes cell sensitivity to T-DM1, and exhibits synergistic activity with T-DM1 to inhibit the formation of spheroids on Matrigel. The discovery described in this manuscript reveals a novel approach to investigate the primary resistance of HER2-positive breast cancer cells and provides an opportunity to develop a therapeutic strategy to overcome primary resistance to T-DM1 by combing T-DM1 therapy with kinase inhibitors of EGFR.

Ambient air pollutants, diabetes and risk of newly diagnosed drug-resistant tuberculosis.

BACKGROUND: Drug-resistant tuberculosis (DR-TB), diabetes and exposure to air pollution are thought to be important threat to human health, but no studies have explored the effects of ambient air pollutants on DR-TB when adjusting diabetes status so far. METHODS: We performed a study among 3759 newly diagnosed TB cases with drug-susceptibility testing results, diabetes status, and individual air pollution data in Shandong from 2015 to 2019. Generalized linear mixed models (GLMM) including three models (Model 1: without covariates, Model 2: adjusted by diabetes status only, Model 3: with all covariates) were applied. RESULTS: Of 3759 TB patients enrolled, 716 (19.05%) were DR-TB, and 333 (8.86%) had diabetes. High exposure to O3 was associated with an increased risk of RFP-resistance (Model 2 or 3: odds ratio (OR) = 1.008, 95% confidence intervals (CI): 1.002-1.014), ethambutol-resistance (Model 3: OR = 1.015, 95%CI: 1.004-1.027) and any rifampicin+streptomycin resistance (Model 1,2,3: OR = 1.01, 95%CI: 1.002-1.018) at 90 days. In contrast, NO2 was associated with a reduced risk of DR-TB (Model 3: OR = 0.99, 95%CI: 0.981-0.999) and multidrug-resistant TB (MDR-TB) (Model 3: OR = 0.977, 95%CI: 0.96-0.994) at 360 days. Additionally, SO2 (Model 1, 2, 3: OR = 0.987, 95%CI: 0.977-0.998) showed a protective effect on MDR-TB at 90 days. PM2.5 (90 days, Model 2: OR = 0.991, 95%CI: 0.983-0.999), PM10 (360 days, Model 2: OR = 0.992, 95%CI: 0.985-0.999) had protective effects on any RFP+SM resistance. CONCLUSIONS: O3 contributed to an elevated risk of TB resistance but PM2.5, PM10, SO2, NO2 showed an inverse effect. Air pollutants may affect the development of drug resistance among TB cases by adjusting the status of diabetes.

Pattern of primary tuberculosis drug resistance and associated risk factors at Dubai health authority in Dubai.

Background: The objective of this study is to determine the initial drug resistance pattern among new tuberculosis (TB) cases and assess the extent of association with human immunodeficiency virus (HIV) and diabetes mellitus (DM). Method: This is a retrospective analysis of 1116 clinical isolates were collected from patients who were newly diagnosed with TB at TB Laboratory between January 2016 and November 2019 and used for determining drug-resistance profiles against five first-line and five second-line anti-TB drugs; and the results were assessed the association between TB risk factors and primary drug resistance TB. Results: Of the 1116 newly diagnosed TB patients, 193 (17.3%) showed resistance to at least one or more of the first-line drugs by different patterns, 105 (9.4%) showed resistance to one drug, 38 (3.40%) showed polyresistance, 50 (4.5%) showed multidrug resistant (MDR), and one patient had extensively drug resistant. Mono-resistance to isoniazid (INH), STR, pyrazinamide, and rifampicin were seen in 40 (3.6%), 33 (2.95%), 29 (2.59%), and 3 (0.3%) of isolates, respectively. INH showed the highest percentage of resistance among the patients. Of 1116 newly diagnosed TB patients, 256 (22.9%) were TB-DM cases and 135 (12.9%) were TB-no DM cases. The rates of drug resistance-TB 46/1116 (4.12%), monoresistance 25 (2.24%), polyresistance 9 (0.8%), and MDR 12 (1.07%) among TB-DM group were higher than TB-no DM group. Conclusion: Our study confirms that resistance to INH was the most common phenomenon. We found that diabetes was identified as a risk factor of TB drug resistance. We did not find a significant association between HIV co-infection and TB drug-resistance.

Primary drug resistance of mycobacterium tuberculosis in Shandong, China, 2004-2018.

BACKGROUND: Primary drug-resistant tuberculosis (DR-TB) has contributed to a significant health and economic burden on a global scale, especially in China. we sought to estimate epidemiological characteristics of primary DR-TB in China from 2004 to 2018. METHODS: Eleven thousand four hundred sixty-seven newly diagnosed and 1981 retreated TB cases with drug susceptibility data were included. Chi-Square test for trends, linear regression, a joinpoint regression model and temporal trend in proportions of the different resistance patterns were carried out. RESULTS: The proportion of primary DR-TB and mono-resistant TB (MR-TB) in China had reduced by more than 12% since 2004, and were 21.38%, 13.35% in 2018 respectively. Among primary DR-TB cases (2173,18.95%), the percentage of multiresistant TB (MDR-TB, from 5.41 to 17.46%), male (from 77.03 to 84.13%), cavity (from 13.51 to 43.92%), rifampicin(RFP)-resistant TB (from 8.11 to 26.98%), streptomycin(SM)-resistant TB (from 50.00 to 71.43%) increased significantly (P < 0.05). On the contrary, the proportion of female, non-cavity, isoniazide(INH)-resistant TB (from 55.41 to 48.15%) and MR-TB (from 82.43 to 62.43%) decreased significant (P < 0.05). The primary drug resistance rate among female, cavity, smoking, drinking, 15 to 44 year-old TB subgroups increased by 0.16, 6.24, 20.95, 158.85, 31.49%, respectively. The percentage of primary DR-TB, RFP-resistant TB dropped significantly during 2004-2007 in Joinpoint regression model. CONCLUSION: The total rate of drug resistance among new TB cases showed a downward trend in Shandong, China, from 2004 to 2018. Primary drug resistance patterns were shifting from female, non-cavity, INH-resistant TB, and MR-TB groups to male, cavity, RFP/SM-resistant TB, and MDR-TB groups. Considering the rising drug resistance rate among some special population, future control of primary DR-TB in China may require an increased focus on female, cavity, smoking, drinking, or 15 to 44 year-old TB subgroups.

Primary drug resistance among tuberculosis patients with diabetes mellitus: a retrospective study among 7223 cases in China.

BACKGROUND: Given the high burden of tuberculosis (TB) and diabetes mellitus (DM) in China and the worse outcome of TB-DM cases (refers to TB patients with diabetes), and drug-resistant tuberculosis cases (DR-TB), it is of great significance to explore the association between diabetes and primary DR-TB for TB elimination target in China. We assessed the clinical characteristics, drug-resistance profile, and increased risk of resistance among TB-DM patients across China from 2004 to 2017. METHOD: 7223 cases with drug-susceptibility data were collected from Shandong, China. Categorical baseline characteristics of new TB cases were compared by DM status using Fisher's exact or Pearson Chi-square test. Univariable analysis and multivariable logistic models were used to estimate the association between diabetes and different drug-resistance profiles and the risk factors of primary drug resistance among TB-DM cases. RESULT: Of 7223 newly diagnosed TB patients, 426 (5.90%) were TB-DM cases. TB-DM csaes were more likely to be older，accompanied by higher body mass index (BMI) and hypertension than TB-no DM cases (refers to TB patients without diabetes). The rates of DR-TB (21.83% vs 16.96%), polydrug resistant TB (PDR-TB, 6.10% vs 3.80%), isoniazid (INH)+streptomycin (SM)-resistant TB (4.93% vs 3.13%), and SM-resistant TB (16.20% vs 11.7%) among TB-DM group were higher than TB-no DM group, P<0.05. DM was significantly associated with any DR-TB (adjusted (aOR):1.30; 95% CI, 1.02-1.65), SM-related resistance (aOR: 1.43; 95% CI, 1.08-1.88), PDR-TB (OR: 1.57; 95% CI, 1.04-2.36; aOR: 1.59; 95% CI, 1.04-2.44), compared with pan-susceptible TB patients (P<0.05). CONCLUSION: Our study indicated that TB-DM groups had a higher proportion of drug resistance than TB groups, and diabetes was identified as a risk factor of total DR, PDR, SM resistance and INH+SM resistance among newly diagnosed TB cases. Good management of diabetes and TB infection screening program among DM patients might be necessary for improving TB control in China.

Primary drug resistance to integrase inhibitors among newly diagnosed HIV infected patients in Shenyang city / 临床检验杂志

Objective@#To explore the transmission of integrase inhibitors (InIs) resistant strains among newly diagnosed HIV-1 infected individuals in Shenyang city. @*Methods@#Eighty newly diagnosed HIV infected individuals were retrospectively collected in Shenyang from June 2018 to March 2019. The sequences of integrase-encoding genes were amplified from the viral RNA in plasma. The viral genotypes were analyzed with phylogenetic method and the mutations of drug resistance genes were interpreted according to the algorithm of Stanford HIV drug resistance database. The primary drug resistance rates were calculated and natural polymorphisms on InIs resistance sites in different subtypes of the virus strain were analyzed. @*Results@#Among the 80 HIV-1 infected individuals, 51, 14 and 6 cases were genotyped as HIV CRF01_AE, CRF07_BC and subtype B respectively, accounting for 63.8%,17.5% and 7.5%. Nine cases (11.3%) were classified as atypical HIV-1 recombinants. R263K mutation was detected in two CRF01_AE infected patients, and E138A mutation was detected in a patient infected with subtype B. The overall drug resistance rate for InIs was 3.8%. CRF01_AE infected individuals showed amino acid polymorphism at the site 50, 74, 119 and 153 relevant to InIs resistance with frequency of 5.9%, 2.0%, 13.7% and 4.0% respectively. The CRF07_BC infected individuals showed amino acid polymorphism at the site 50, 74 and 157 relevant to InIs resistance with frequency of 7.1% for each site. @*Conclusion@#The primary drug resistance rate of InIs among the newly diagnosed HIV infected people in Shenyang was low, but a small number of patients showed amino acid polymorphisms on InIs resistance sites. To interpret the significance of drug resistance mutations in InIs better, it is necessary to strengthen both the monitoring of HIV InIs resistance and the study on the drug resistance-relevant genotype and phenotype of HIV-1 strains epidemic in China.

Baseline Investigation of HIV-1 Primary Drug Resistance Among Newly Diagnosed Treatment-Naïve HIV-1 Individuals in Hebei, China.

Human immunodeficiency virus (HIV) primary drug resistance (PDR) has influenced the long-term therapeutic effects of antiretroviral drugs. However, for the overall PDR prevalence in China, no report was found in published articles. In our study, an extensive cross-sectional investigation based on all newly diagnosed treatment-naive HIV-infected individuals was conducted. The overall prevalence of HIV-1 PDR among newly diagnosed treatment-naive HIV-1 individuals was 8.3% (60/720), obviously beyond the warning line (5.0%) set by WHO. The prevalence of PDR to PIs, nucleoside reverse transcriptase inhibitors, and non-nucleoside reverse transcriptase inhibitors was 4.9% (35/720), 0.4% (3/720), and 2.5% (18/720), respectively. Moreover, the occurrence of HIV-1 PDR strains was random among different prefectures. HIV-1 PDR strains were extensively circulating among the sexual contact population inside and outside the Hebei province, especially between neighboring provinces and Hebei. Hebei province has become the moderate level PDR epidemic area. Enhanced surveillance for PDR is necessary among treatment-naïve individuals in Hebei, and we must take effective measures to cut off the spread of HIV PDR strains.

Subtypes and primary drug-resistant gene mutations in HIV-1 infections in Jiangyin / 中华实验和临床病毒学杂志

Objective@#To investigate the subtypes and primary drug resistant (PDR)mutations among HIV-1 infected population in Jiangyin.@*Methods@#Anticoagulated blood samples were collected from HIV infected individuals confirmed and managed by Jiangyin CDC from 2013-2015, and epidemiological data were analyzed. The pol gene was amplified by nested-PCR from the DNA extraction and then sequenced. Phylogenetic tree was constructed to determine the subtypes of the samples. PDR mutations and viral susceptibility to ARTs were interpreted with the Surveillance Drug Resistance Mutations (SDRM)list recommended by WHO and Stanford University HIV Drug Resistance database.@*Results@#The pol gene of 100 cases was successfully amplified and sequenced among 111 samples enrolled in this study, 7 different subtypes were found by phylogenetic tree analysis and CRF01_AE(44/100), CRF07_BC(21/100), CRF67_01B(14/100)subtypes accounted for the main part. Fourteen participants (14/100)met the WHO guidelines of having HIV-1 PDR. NRTI, NNRTI, PI PDR mutation rates were 3.0%, 7.0%, and 6.0%, respectively. Nine cases of the 14 infections with PDR presented clinical DR and the resistance rate was 8.1%, of which CRF01_AE accounted for the main part (5/9).@*Conclusions@#The prevalence of HIV-1 infections of different subtypes in Jiangyin city varied and there was a certain proportion of primary drug resistance. Corresponding drug resistance testing should be carried out for new HIV infections before treatment and reasonable antiviral treatment plan should be formulated, which will reduce the emergence of drug-resistant strains ultimately.