Trend of HIV Transmitted Drug Resistance After the Introduction of Single-Tablet Regimens in Southern Taiwan.

Background: The prevalence of transmitted drug resistance (TDR) after the universal implementation of STRs is unknown in Taiwan. Objective: This study aimed to investigate the prevalence of TDR in patients with HIV-1 infection, clarify the risk factors for pol resistance, and compare differences in HIV drug resistance before and after the implementation of STRs in Taiwan. Methods: Adult patients infected with HIV-1 were enrolled in this study from 2013 to 2021. Mutations associated with drug resistance were identified using the 2019 International Antiviral Society-USA list of drug resistant mutations in HIV, and drug susceptibility was assessed according to the Stanford HIV Drug Resistance Database edition 9. A logistic regression model was used to analyze the risk factors for pol resistance, and the differences in the prevalence of drug resistance from 2013-2016 to 2017-2021 were compared using the Mann-Whitney U-test. General linear regression was used to analyze temporal changes in the annual proportion of TDR overall and by type of antiretroviral drugs. Results: A total of 369 patients were included. The prevalence rate of pol resistance was 9.8% (36/369). The resistance rates to nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors (PIs), and integrase strand transfer inhibitors (INSTIs) were 3.3%, 6.9%, 0% and 1.8%, respectively. The patients with hepatitis C infection were more likely to have pol resistance (aHR 5.767, CI 1.232-26.991, p=0.026). The prevalence rate of pol resistance did not decrease after the implementation of STRs as first-line therapy in 2017 (11.2% vs 8.7%, aHR 1.329, CI 0.667-2.645, p=0.480), and no significant temporal changes were shown in the annual proportion of TDR overall or by type of antiretroviral drug. Conclusion: Our findings showed a stable prevalence rate of transmitted drug resistance despite the implementation of STRs as the first-line therapy in June 2016.

High Prevalence of Doravirine Resistance in HIV-1-Infected Patients with Virological Failure to an NNRTI-Based Single-Tablet Regimen.

Purpose: This study aimed to investigate the prevalence of resistance to a non-nucleoside reverse transcriptase inhibitor (NNRTI)-based single-tablet regimen (STR) in Taiwanese patients and clarify the clinical implications of using doravirine in patients who fail NNRTI treatment. Patients and Methods: Taiwanese patients infected with HIV-1 who failed NNRTI-based STR treatment were enrolled in this retrospective cohort study from 2015 to 2020. Mutations associated with drug resistance were identified using the 2019 International Antiviral Society-USA list of drug-resistant mutations in HIV, and drug susceptibility was assessed according to the Stanford HIV Drug Resistance Database version 9. Median values of continuous variables were compared between two groups using the Mann-Whitney U-test, and categorical variables were compared using the chi-square test or Fisher's exact test. Results: A total of 107 patients were included, of whom 29 were treatment failure to the initial STRs, and 78 failed treatment after switching to an STR. Seventy-four patients failed treatment with TDF/FTC/EFV (Atripla), 30 with TDF/FTC/RPV (Complera) and 3 with TAF/FTC/RPV (Odefsey). The prevalence rates of resistance to nucleoside reverse transcriptase inhibitors (NRTIs), NNRTIs, protease inhibitors (PIs) and integrase strand transfer inhibitors (INSTIs) were 76%, 86%, 3% and 2%, respectively. Among the 29 patients failure to the initial STRs, 62% developed doravirine resistance, compared to 64% of the 78 the patients who failed treatment after switching to an STR. There were no significant differences in the prevalence of specific NNRTI or doravirine resistance-associated mutations between these two groups. The patients with K65R mutations were more likely to have NNRTI resistance (p = 0.037) and doravirine resistance (p < 0.001). Conclusion: Our findings showed a high rate of doravirine cross-resistance in patients with NNRTI-based STR treatment failure. Doravirine should be used cautiously as a salvage regimen in patients who fail NNRTI treatment.

COVID-19 vaccines: concerns beyond protective efficacy and safety.

INTRODUCTION: Several vaccine candidates have been developed using different platforms, including nucleic acids (DNA and RNA), viral vectors (replicating and non-replicating), virus-like particles, peptide-based, recombinant proteins, live attenuated, and inactivated virus modalities. Although many of these vaccines are undergoing pre-clinical trials, several large clinical trials investigating the clinical efficacy and safety of coronavirus disease 2019 (COVID-19) vaccines have produced promising findings. AREAS COVERED: In this review, we provide a status update on COVID-19 vaccines currently undergoing clinical trials and discuss issues of concern beyond vaccine efficacy and safety, including dosing regimens, the mixed vaccine strategy, prior severe acute respiratory syndrome coronavirus-2 infection, antibody levels, cellular immunity and protection, variants of concern, COVID-19 vaccine distribution, vaccination willingness, herd immunity, immunity passports, and vaccine indications. EXPERT OPINION: Four vaccines have obtained emergency use authorization, 87 are at the clinical development stage, and 186 are in pre-clinical development. While the knowledge and development of COVID-19 vaccines is rapidly expanding, the benefits of COVID-19 vaccines must outweigh the potential risks of adverse events. To combat the COVID-19 pandemic, clinicians should consistently update COVID-19-associated information, and healthcare authorities and manufacturers should work together to provide adequate and appropriate vaccinations for the prevention of COVID-19. PLAIN LANGUAGE SUMMARY: What is the context?Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) caused a global pandemic: the coronavirus disease 2019 (COVID-19) outbreak. The development and implementation of the COVID-19 vaccine could be an important measure to control the COVID-19 pandemic.What is new?Several phase 3 clinical trials have demonstrated the effectiveness and safety of COVID-19 vaccines for the prevention of SARS-CoV-2 infections. Several COVID-19 vaccines have obtained emergency use authorization and been implemented in many countries. Although concerns regarding unusual blood clots and low platelet counts have been raised, the benefits of COVID-19 vaccines outweigh the potential risks of adverse events.What is the impact?Except for children, the COVID-19 vaccine is recommended for all people, including those pregnant or immunocompromised. Healthcare authorities should advise people receiving the vaccine that they must seek medical attention if they have associated thromboembolism and thrombocytopenia symptoms. More studies are necessary to determine the appropriate vaccine dose and regimen strategy, as well as the effectiveness of COVID-19 vaccines against variants of concerns. A global effort must be made to achieve widespread vaccination and herd immunity.

Prevalence of HIV-1 Integrase Strand Transfer Inhibitor Resistance in Treatment-Naïve Voluntary Counselling and Testing Clients by Population Sequencing and Illumina Next-Generation Sequencing in Taiwan.

PURPOSE: Integrase strand transfer inhibitors (INSTIs) are used as first-line therapy for HIV-1-infected patients. Next-generation sequencing (NGS) can detect low-frequency mutants; however, the clinical value of NGS to detect resistance variants is unknown. This study aimed to evaluate the prevalence of INSTI resistance in southern Taiwan and determine the clinical implications of using NGS to detect integrase region low-level resistant variants. PATIENTS AND METHODS: This retrospective cohort study included antiretroviral therapy-naïve HIV-1-infected individuals at Kaohsiung Veterans General Hospital, Taiwan, from 2013 to 2017. Drug-resistance mutations were determined, and an in-house polymerase chain reaction was used for genotyping INSTI resistance. NGS was used to assess INSTI resistance (≧1%), and the results were compared with those from population sequencing. Drug resistance-associated mutations were defined according to the 2019 IAS-USA HIV drug resistance-associated mutations list, and accessory mutations by a Stanford HIVdb score ≥10 to at least one INSTI. RESULTS: A total of 224 patients were included. Subtype B HIV-1 strains were found in 96% of the individuals and subtype CRF01_AE in 4%. The prevalence rates for nucleoside reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, protease inhibitors and INSTI resistance were 4%, 5.8%, 0.4% and 0.9%, respectively. The most common INSTI resistance-associated mutations were G163K (0.4%) and E138A (0.4%). Of the 38 patients diagnosed in 2017 who had both NGS and population sequencing data, none had INSTI resistance-associated mutations by population sequencing; however, NGS detected four more INSTI resistance-associated mutations with low frequencies (G163R 3.25%, S153F 3.21%, S153Y 1.36% and Y143H 2.06%). Two patients with S153F and S153Y low frequencies mutations started INSTI-based highly active antiretroviral therapy, and none had virological failure by week 48. CONCLUSION: Our findings showed a low rate of HIV drug resistance to INSTIs (0.9%) in treatment-naïve patients. NGS detected more INSTI resistance-associated mutations at a low frequency. Low-level drug resistance-associated mutations to INSTIs identified by NGS did not have an impact on the treatment response to INSTI-based first-line therapy.

Trend of HIV transmitted drug resistance before and after implementation of HAART regimen restriction in the treatment of HIV-1 infected patients in southern Taiwan.

BACKGROUND: The use of fixed combination antiretroviral therapy with a low genetic barrier for the treatment of patients infected with human immunodeficiency virus (HIV) may affect the local HIV transmitted drug resistance (TDR) pattern. The present study aimed to investigate changes in the prevalence of HIV TDR following the implementation of a fixed regimen of HIV treatment in Taiwan in 2012. METHODS: TDR was measured in antiretroviral treatment-naïve HIV-1-infected individuals who participated in voluntary counseling and testing between 2007 and 2015 in southern Taiwan. Antiretroviral resistance mutations were interpreted using the HIVdb program from the Stanford University HIV Drug Resistance Database. RESULTS: Sequences were obtained from 377 consecutive individuals between 2007 and 2015. The overall prevalence rates of TDR HIV among the study population from 2007 to 2011 and 2012-2015 were 10.6 and 7.9%, respectively. Among the detected mutations, K103 N and V179D + K103R were more frequently observed after 2012. Four HIV-infected patients with K103 N variants were detected after 2012, and 4 of the 5 patients with V179D + K103R variants were found after 2012. No significant differences were observed in the TDRs among nucleoside reverse transcriptase inhibitors (NRTIs), non-NRTIs (NNRTIs), protease inhibitors, multiple drug resistance, and any drug resistance between period 1 (2007-2011) and period 2 (2012-2015). CONCLUSIONS: A fixed treatment regimen with zidovudine/lamivudine + efavirenz or nevirapine as first-line therapy for treatment-naïve patients infected with HIV did not significantly increase the TDR during the 4-year follow-up period. Due to the increase in NNRTI resistance associated with mutations after 2012, a longer follow-up period and larger sample size are needed in future studies.

HIV-1 genotypic drug resistance in patients with virological failure to single-tablet antiretroviral regimens in southern Taiwan.

PURPOSE: Sparse data are available on the prevalence of resistance among HIV-1-infected patients with virological failure to a single-tablet regimen (STR). This study aimed to evaluate the prevalence of HIV genotypic drug resistance in HIV-1-infected patients with virological failure to STRs in southern Taiwan. PATIENTS AND METHODS: This retrospective study investigated drug resistance in patients with virological failure to STR from January 2016 to September 2017. Antiretroviral resistance mutations were defined using the 2017 International AIDS Society-USA HIV drug resistance algorithm, and drug resistance was compared using the HIVdb program of the Stanford University HIV Drug Resistance Database. Variables between resistance and non-resistance groups were compared. RESULTS: Thirty-nine HIV-1-infected patients with treatment failure were tested for resistance, of whom 89% were infected by men who have sex with men. Subtype B HIV-1 strains were found in 90% of the patients. Eight patients were treatment naïve and initiated STRs, while 31 patients experienced treatment failure after switching to STRs. Eighty-seven percent of the patients harbored any of four classes of resistance (nucleoside reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, protease inhibitors (PIs), and integrase strand transfer inhibitors). The prevalence rates of nucleoside reverse transcriptase inhibitor, non-nucleoside reverse transcriptase inhibitor, PI, and integrase strand transfer inhibitor resistance were 72%, 82%, 10%, and 3%, respectively. Patients with PI resistance were more likely to respond to treatment with a non-tenofovir disoproxil fumarate/emtricitabine/efavirenz-based STR (.=0.004) and a longer duration of antiretroviral therapy (101 months [72.0-123.3] vs 11 months [7-44], P=0.007). There were no associations between different STRs and transmission risk factors, HIV subtype, duration of antiretroviral therapy, and resistance to tenofovir disoproxil fumarate. CONCLUSION: A high rate of antiretroviral drug resistance was found in the patients who failed STR treatment. The presence of PI resistance in these patients represented an inappropriate switch from a multiple tablet regimen to an STR. These findings should remind clinicians that detailed drug resistance history and close monitoring are mandatory after switching to an STR.

HIV-1 integrase strand-transfer inhibitor resistance in southern Taiwan.

The use of antiretroviral therapy has reduced rates of mortality and morbidity in patients with human immunodeficiency virus/acquired immune deficiency syndrome(HIV/AIDS). However, transmission of drug-resistant strains poses a challenge to control the spread of HIV-1. Primary resistance to integrase strand-transfer inhibitors (INSTIs) is rare despite their increased use. The prevalence of transmitted drug resistance (TDR) to INSTIs was 0.9% in northern Taiwan. This study was to analyse the prevalence and risk factors of TDR to INSTIs in southern Taiwan. In this study, we enrolled antiretroviral treatment-naïve HIV-1-infected subjects who underwent voluntary counselling and testing from 2013 to 2016 in southern Taiwan. Genotypic drug resistance, coreceptor tropism (CRT) and INSTI resistance were determined. Logistic regression was used to analyse the risk factors for INSTI polymorphic substitution. Sequences were obtained from 184 consecutive individuals, of whom 96.7% were men who have sex with men and 3.3% were heterosexual. Of the patients, 10% (19/183) had hepatitis B and 33.3% (61/183) had syphilis infection. Subtype B HIV-1 strains were found in 96.1% of the patients. Fifteen patients (8.4%, 15/178) harboured nucleoside reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors or protease inhibitors resistance. CCR-5 coreceptors were used by 71.4% (130/184) of the patients. None of the patients had INSTI resistance-associated mutations, however 16 patients had INSTI polymorphic substitutions, and they were associated with a higher HIV viral load (p = 0.03, OR 2.4, CI 1.1-5.3) and syphilis infection (p = 0.03, OR 3.7, CI 1.1-12.0). In conclusion, no signature INSTI resistance-associated mutations were detected in our cohort. Continued monitoring of TDR to INSTI is needed due to the increased use of INSTIs.

High rate of HIV-1 drug resistance in treatment failure patients in Taiwan, 2009-2014.

BACKGROUND: Drug resistance to nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), and protease inhibitors (PIs) has been associated with loss of viral suppression measured by a rise in HIV-1 RNA levels, a decline in CD4 cell counts, persistence on a failing treatment regimen, and lack of adherence to combination antiretroviral therapy. OBJECTIVES: This study aimed to monitor the prevalence and risk factors associated with drug resistance in Taiwan after failure of first-line therapy. MATERIALS AND METHODS: Data from the Veterans General Hospital Surveillance and Monitor Network for the period 2009-2014 were analyzed. Plasma samples from patients diagnosed with virologic failure and an HIV-1 RNA viral load >1000 copies/mL were analyzed by the ViroSeq™ HIV-1 genotyping system for drug susceptibility. Hazard ratios (HRs) for drug resistance were calculated using a Cox proportional hazard model. RESULTS: From 2009 to 2014, 359 patients were tested for resistance. The median CD4 count and viral load (log) were 214 cells/µL (interquartile range [IQR]: 71-367) and 4.5 (IQR: 3.9-5.0), respectively. Subtype B HIV-1 strains were found in 90% of individuals. The resistance rate to any of the three classes of antiretroviral drugs (NRTI, NNRTI, and PI) was 75.5%. The percentage of NRTI, NNRTI, and PI resistance was 58.6%, 61.4%, and 11.4%, respectively. The risk factors for any class of drug resistance included age ≤35 years (adjusted HR: 2.30, CI: 1.48-3.56; p<0.0001), initial NNRTI-based antiretroviral regimens (adjusted HR: 1.70, CI: 1.10-2.63; p=0.018), and current NNRTI-based antiretroviral regimens when treatment failure occurs (odds ratio: 4.04, CI: 2.47-6.59; p<0.001). There was no association between HIV-1 subtype, viral load, and resistance. CONCLUSION: This study demonstrated a high level of resistance to NRTI and NNRTI in patients with virologic failure to first-line antiretroviral therapy despite routine viral load monitoring. Educating younger men who have sex with men to maintain good adherence is crucial, as PI use is associated with lower possibility of drug resistance.

Stability Limit of Water by Metastable Vapor-Liquid Equilibrium with Nanoporous Silicon Membranes.

Liquid can sustain mechanical tension as its pressure drops below the vapor-liquid coexistence line and becomes less than zero, until it reaches the stability limit-the pressure at which cavitation inevitably occurs. For liquid water, its stability limit is still a subject of debate: the results obtained by researchers using a variety of techniques show discrepancies between the values of the stability limit and its temperature dependence as temperature approaches 0 °C. In this work, we present a study of the stability limit of water by the metastable vapor-liquid equilibrium (MVLE) method with nanoporous silicon membranes. We also report on an experimental system which enables tests of the temperature dependence of the stability limit with MVLE. The stability limit we found increases monotonically (larger tension) as temperature approaches 0 °C; this trend contradicts the centrifugal result of Briggs but agrees with the experiments by acoustic cavitation. This result confirms that a quasi-static method can reach stability values similar to that from the dynamic stretching technique, even close to 0 °C. Nevertheless, our results fall in the range of ∼ -20 to -30 MPa, a range that is consistent with the majority of experiments but is far less negative than the limit obtained in experiments involving quartz inclusions and that predicted for homogeneous nucleation.

Beamformer-based spatiotemporal imaging of linearly-related source components using electromagnetic neural signals.

Functional connectivity calculated using multiple channels of electromagnetic brain signals is often over- or underestimated due to volume conduction or field spread. Considering connectivity measures, coherence is suitable for the detection of rhythmic synchronization, whereas temporal correlation is appropriate for transient synchronization. This paper presents a beamformer-based imaging method, called spatiotemporal imaging of linearly-related source component (SILSC), which is capable of estimating connectivity at the cortical level by extracting the source component with the maximum temporal correlation between the activity of each targeted region and a reference signal. The spatiotemporal correlation dynamics can be obtained by applying SILSC at every brain region and with various time latencies. The results of six simulation studies demonstrated that SILSC is sensitive to detect the source activity correlated to the specified reference signal and is accurate and robust to noise in terms of source localization. In a facial expression imitation experiment, the correlation dynamics estimated by SILSC revealed the regions with mirror properties and the regions involved in motor control network when performing the imitation and execution tasks, respectively, with the left inferior frontal gyrus specified as the reference region.