Detection of ARV-Resistant Mutants in HIV-1-Infected Individuals in a Context of Systematic Switching to an Association Based on Dolutegravir in Abidjan, Côte d’Ivoire

The emergence of antiretroviral resistance mutations represents a major threat to the achievement of national and global goals for the elimination of HIV-1 infection. The global strategy in 2019 in Cte d'Ivoire is a new national policy for the management of people living with HIV with the administration of dolutegravir (DTG)-based fixed-dose combination. The aim of our study was to evaluate HIV-1 resistance to antiretrovirals (ARVs) in infected adult subjects in Cte d’Ivoire in the context of a systematic switch to a DTG-based combination. Between February 2022 and October 2023, a cross-sectional survey with random sampling was conducted in 06 services caring for people living with HIV. A total of 139 participants were included in the study. Adults with a viral load ≥ 1000 copies/mL were tested for HIV-1 ARV resistance mutations. Molecular analyses were performed using protocol of ANRS-MIE (National Agency for Research on AIDS and emerging infectious diseases). The interpretation is performed by HIVGRAD (https://www.hiv-grade.de/cms/grade/). The frequencies of HIV-1 resistance to non-nucleotide reverse transcriptase inhibitors (NNRTIs), nucleotide reverse transcriptase inhibitors (NRTIs), integrase inhibitors (IINTs) and protease inhibitors (PIs) were 82%, 73%, 19% and 11% respectively. The main mutations observed in the different classes were K103N (45%), M184V (64%), E157Q (19%) and L10V/M46I/A71V/I54V (6%) respectively. This study reveals the emergence of resistance to DTG-based fixed-dose combinations, favored by high rates of resistance to NRTIs and NNRTIs. This finding underlines the need for enhanced viral load monitoring and HIV-1 genotyping tests to guide the choice of NRTIs for combination therapy. In addition, monitoring for mutations to second-generation NRTIs is essential, given the scale-up of DTG-based regimens currently underway in Cte d’Ivoire.

Neurocognitive Profile of People Living with Human Immunodeficiency Virus Initiating Treatment in Kinshasa in the Dolutegravir Era, Democratic Republic of Congo

Context: Antiretroviral therapies improve the prognosis of NeuroAIDS contrasting with a high frequency of Minor Neurocognitive Disorders (MND) even in aviremic subjects. Objective: The objective of this study is to present the neurological and cognitive profile of People Living with HIV (PLHIV) initiating antiretroviral treatment in Kinshasa in the era of Dolutegravir (DTG). Methods: This is a multicenter, cross-sectional study with a descriptive aim carried out in 16 HIV Outpatient Treatment Centers (OTC) in Kinshasa from October 4, 2021 to February 15, 2022. The International HIV Dementia Scale (IHDS) correlated with the Activities of Daily Living (IADL) scale facilitated the categorization of NeuroCognitive Disorders (NCD) of PLHIV evaluated after carrying out a summary neurological examination. Results: Of the 96 patients recruited, 56.3% were women with a sex ratio of 0.68. The average age was 40.1 ± 12.1 years. The secondary education level was the majority at 64.6%. Malaria (44.8%) and tuberculosis (32.3%) were more common as opportunistic infections. They were alcoholics in (30.2%). Their history was heart disease (15.6%), high blood pressure (18.8%);drug abuse (10.4%). The IHDS score was light in 55.2% of cases. The correlation between IHDS/IADL watches asymptomatic neurocognitive impairments (ANI) in 77.1%, almost all of subjects are found with normal overall functioning (94.8%) and a disturbed neurological examination in 53.1% of cases with a predominance of motor impairments in 79.1%. Conclusion: In view of these results, early and systematic screening of NCD and associated factors remains necessary in our context. .

Profile of People Living with Human Immunodeficiency Virus Initiating Treatment in the Dolutegravir Era in Kinshasa, Democratic Republic of Congo

Background: For several decades, the introduction of AntiRetrovirals (ARVs) has improved the symptomatology of People Living with HIV (PLHIV), a spectacular reduction in morbidity and mortality, an improvement in life expectancy and quality of life of PLHIV. Objective: The objective of this study was to determine the profile of PLHIV initiating AntiRetroViral Treatment (ART) in the era of Dolutegravir in Kinshasa. Methods: Cross-section of a prospective cohort to determine the profile of PLHIV initiating ART in Kinshasa. The inclusions were from October 04, 2021 to February 15, 2022. Confirmation of the diagnosis was carried out by Nested PCR. The inclusion criteria were: being at least 18 years old, confirmed HIV positive, naïve to ART, consenting and having signed an informed consent. The parameters of interest followed for the present study were: age, sex, religion, level of study, marital status, occupation, height, weight, body mass index (BMI), the clinical profile, the opportunistic infections as well as the para-clinical assessment (biochemistry and molecular biology). Results: 67 (56.3%) women and 52 (43.7%) men were included, thus 119 patients, all confirmed positive for HIV by Nested PCR on the gag, pol and env regions. The average age of the patients included is 39.87 ± 12.36 years and the most represented age group is that of 36 to 45 years with 37 patients (31.9%). The average height was 1.66 ± 0.08 meters, with an average weight of 56.41 ± 13.30 kg, giving an average Body Mass Index (BMI) of 21.54 ± 5.17 kg/m2. The majority of patients were married (46.1%), of Protestant religion (70.7%), with secondary education (66.7%), and working in the informal sector (29.4%). 49 patients (41.5%) were in clinical stage 3 and 55 patients (47.0%) had a normal clinical status. Malaria (45.4%) and tuberculosis (29.4%) were the most common Opportunistic Infections. The mean values of the patients’ assessed biochemical parameters were within the ranges. The median VL value was 4.16 log10 RNA copies/ml. Subtype A (20.2%) is dominant. Mutations K65R (2 cases), T69P/N (5 cases), K70R (9 cases) and M184V (8 cases) were listed. Conclusion: In Kinshasa, PLHIV start ART late. The biochemical parameters evaluated are within normal ranges, with high VLs. Subtype A remains predominant and there are mutations conferring resistance to ART.

Virological and Molecular Profile of People Living with HIV after 24 Weeks of Treatment with Dolutegravir in Kinshasa

Context: The appointment of the M6 is crucial because it is an indicator of the prognosis of the evolution of the care and the decision-making on the continuation of the AntiRetroViral Treatment. Objective: The objective of this study is therefore to present the virological and molecular profile of People Living with HIV under treatment with Dolutegravir 6 months after being put on ART in Kinshasa. Methods: The present study is a cross-sectional view at the sixth month of a prospective cohort to determine the virological and molecular profile of People Living with HIV (PLHIV) after 6 months of ART based on Dolutegravir (DTG) in Kinshasa. A sample of 5 mL of blood was taken from all HIV patients included. The collection of biological data was carried out under the same conditions as at inclusion. After extraction, Quantitative Real-Time PCR was carried out to determine the quantity of HIV RNA in the samples according to the protocols previously described. Reverse Transcription PCR (RT-PCR) and Nested PCR were carried out to amplify the regions of interest for Protease and Reverse Transcriptase for sequencing. Results: The median VL value was 2.92 log10 RNA copies/mL. With 17.75% of patients experiencing major failure of first-line treatment. Subtype A is dominant with 13 cases (20.98%);followed by CRF_02AG (16.13%), subtypes C (14.52%), D (9.68%) and K (6.45%). The K65R (3 cases), T69P/N (6 cases), K70R (9 cases) and M184V (8 cases) mutations were listed as existing mutations for Nucleotide Reverse Transcriptase Inhibitors. Conclusion: After 6 months of ART, 59.67% of People Living with HIV on Tenofovir-Lamivudine-Dolutegravir is in therapeutic success while 40.33% are in a state of treatment failure. Subtype A remains dominant in the population of PLHIV. Resistance mutations were detected for Lamivudine and Tenofovir, but none for Dolutegravir.

Profile of People Living with HIV after 24 Weeks of Treatment with Dolutegravir in Kinshasa

Introduction: The sixth month appointment (M6) is crucial because at the start of the ART course, it is an indicator of the prognosis of the evolution of care and decision-making on the continuity of treatment. Objective: The objective of this study is therefore to present the profile of People Living with HIV under treatment with Dolutegravir 6 months after starting ART in Kinshasa. Methods: The present study is a cross-sectional view at M6 of a prospective cohort to determine the profile of People Living with HIV (PLHIV) after 6 months of ARV Treatment (ART) in Kinshasa, DRC. During the M6 appointment, from April to August 2022, a sample of 5 ml of blood was taken for the various analyzes from all HIV patients included. The collection of sociodemographic data as well as biological and clinical data was carried out under the same conditions as at inclusion. The parameters recorded during M6 were: age, sex, and religion, level of study, marital status, profession, socio-economic level, height, weight, Body Mass Index (BMI), clinical profile, opportunistic infections as well as biochemical and molecular assessment. Results: In M6, 62 patients were registered including 38 women (61.3%), thus giving a sex ratio of 1.58 in favor of women. Fifty-seven (57) patients did not respond to the appointment, representing a loss rate of 47.89%. The most common age group is between 36 and 45 years old with 16 patients (26.7%). The mean age was 42.4 ± 13.3 years. The mean weight was 60.5 ± 15.4 kg with a mean BMI of 22.6 ± 5.8 kg/m2. Thirty-four (34) patients (61.82%) were in Clinical Stage 3. Thirty-six (36) patients (67.92%) had a normal clinical condition. The most common opportunistic infections among patients in M6 were: skin pruritus (25.8%), dermatitis (22.6%) and rash (21%). The mean values of biochemical parameters of patients in M6 were within normal ranges. The median VL value was 2.92 log10 RNA copies/ml with 17.75% of patients experiencing major failure of first-line treatment. Subtype A is dominant with 13 cases (20.98%);followed by CRF02_AG (16.13%) and C subtypes (14.52%). The mutations K65R (3 cases), T69P/N (6 cases), K70R (9 cases) and M184V (8 cases) were listed in M6. Conclusion: After 6 months of treatment, the majority of patients are in clinical stage 3 with a normal clinical state. Skin infections are the majority opportunistic infections. Certain biological parameters are considerably altered. A high virological failure rate with the presence of certain mutations associated with resistance to Lamivudine and Tenofovir.

Virological Profile of People Living with HIV after 12 Months of Treatment with Dolutegravir in Kinshasa

Context: The evaluation of plasma Viral Load constitutes an indicator of the progression of the infection, the effectiveness and the tolerance of the treatment. Objective: The objective of this study is to present the virological profile of Patients Living with HIV (PLHIV) after 12 months of AntiRetro Viral Treatment (ART) based on Dolutegravir (DTG) in Kinshasa. Method: The present study is a cross-sectional view of the virological profile of the twelfth month of a prospective cohort of PLHIV at M12 of DTG-based ART in Kinshasa. During the M12 appointment, a blood sample was taken for Molecular Biology analyses from all PLHIV included. Result: During the M12 appointment, 28 patients were registered, including 16 (57.1%) women. Nine (9) patients (45.0%) had an undetectable Viral Load (VL). The median VL value was 3.18 log10 RNA copies/mL (1530 RNA copies/mL). The mutations K65R, T69P/N, K70R and M184V have been listed as mutations conferring resistance to Nucleotide Reverse Transcriptase Inhibitors. No mutations associated with Dolutegravir were observed at M12. Conclusion: After 12 months of AntiRetroViral Treatment based on Dolutegravir, half of the Patients on first-line ART are in a state of virological failure.

Compliance with First-Line AntiRetroViral Treatment (ART) for HIV Infection in the Era of Dolutegravir in Kinshasa, Democratic Republic of the Congo

Context: Two years after the transition to Dolutegravir (DTG), at the national level, data on compliance with the execution of this transition and the rational use of the new molecule are not available. Objective: The objective of this study was to determine compliance with first-line ART prescriptions among People Living with HIV starting AntiRetroViral treatment in Kinshasa during the Dolutegravir era. Methods: This study is a descriptive cross-sectional study to determine compliance with first-line ART prescriptions among people living with HIV during the Dolutegravir era in Kinshasa. Sixteen Outpatients Treatment Centers (OTCs) were included in the study for their expertise in the care of PLHIV, their technical collection platform and their accessibility. The parameters of interest were: age, sex, outpatient treatment centers, and medical prescription. Results: One hundred and nineteen (119) patients were included in this work in accordance with the inclusion criteria;67 (56.3%) are female, giving a sex ratio of 1.29 in favor of women. The average age of the patients included is 39.87 ± 12.36 years with extremities of 18 to 69 years. The most represented age group is that of 36 to 45 years with 37 patients (31.9%). One hundred and nineteen (119) patients were received from 16 centers in Kinshasa, according to 6 OTC for the district of Funa, 4 OTC for Tshangu and 3 OTC respectively for Lukunga and Mont-Amba. All the centers respect the new recommendations of the National Program;all patients (100%) are on the Tenofovir (TDF) + Lamivudine (3TC) + Dolutegravir (DTG) combination. Conclusion: Compliance with the prescription of DTG as a first-line ARV in the DRC is effective in the city province of Kinshasa.

第二代整合酶链转移抑制剂dolutegravir

dolutegravir是第二代整合酶链转移抑制剂。与第一代整合酶链转移抑制剂相比，dolutegravir具有更高的耐药发展屏障，可一天1次给药。对已产生对拉替拉韦和elvitegravir耐药的人免疫缺陷病毒感染患者，仍可使用dolutegravir。但用药频率调整为一天2次。dolutegravir用于肝、肾功能损害患者时不需剂量调整。在临床试验中，dolutegravir治疗的最常见不良反应是失眠和头痛，发生率均为2％一3％。作为一种新的整合酶链转移抑制剂，dolutegravir具有疗效显著、耐受性好的特点。

Evaluation of Rational Use of Antiretrovirals before the Dolutegravir Transition in Kinshasa, Democratic Republic of Congo

Background: The ultimate goal of AntiRetroViral Treatments (ART) is to achieve complete immune restoration and lasting viral suppression in the infected patient. In order to ensure the efficacy, safety and accessibility of antiretroviral drugs (ARVs), it is recommended that they should be prescribed according to national guidelines;which are evolving with the various recommendations of the World Health Organization (WHO) and the arrival of newer, more effective and safer molecules. Objective: The objective of this study was to assess the rational use of Antiretrovirals in patients treated in Kinshasa before the use of Dolutegravir within the national program in order to assess the correct use of these molecules. Methods: This work is a descriptive cross-sectional study to assess the rational use of first-line ARVs among People Living with HIV (PLHIV) in different Centers of Treatment (ATCs) in Kinshasa before the introduction of Dolutegravir. The records of patients on ARVs were randomly and rationally selected in 12 different ATCs for HIV in Kinshasa according to three centers per district in the period from June to September 2018. Information on use and consumption of ARVs, compliance with guidelines, change of therapeutic combination as well as their reasons were consulted for the present study. Results: 507 files of PLHIV were collected in the various ATCs. 274 (54.1%) were from female patients. The most represented age group was 26 to 35 years with 192 patients (37.9%). The mean duration of first-line treatment for all patients included was 16.30 ± 5.85 months. The most widely used combination of ARVs overall was TDF + 3TC + EFV at 45.4%. 305 (60.2%) PLHIV kept the same first-line treatment molecule throughout the treatment period with an average treatment duration of 12.9 ± 2.77 months. The most common combination found in this population was TDF + 3TC + EFV (69.2%). 202 (39.8%) PLHIV changed treatment molecule yet respecting the first-line combinations. The average duration of treatment for those who changed molecules was 21.43 ± 7.25 months. Before the change, 112 (55.5%) of these patients were using the ZDV + 3TC + EFV combination. After switching, 105 (52%) of the patients used the TDF + 3TC + NVP combination. The first reason for changing molecules was its unavailability (53.3%) in the ATCs. Conclusion: Although some banned molecules are still available in some treatment centers, the guidelines on first-line treatments are respected in different centers in Kinshasa.

HIV Genetic Diversity, Virological Failure, and Drug Resistance in Libreville, Capital of Gabon, before a Total Dolutegravir-Based Regimen Transition

Context: The Human Immunodeficiency Virus (HIV) continues to be the main public health challenge in Gabon. The latest studies highlight a high rate of virological failure and HIV drug resistance in semi-rural Gabon. In Libreville, virological failure data is sparse, data on HIV drug resistance for the former first line and new first-line regimen is lacking. Methods: Between January 28th, 2019, and January 31st, 2020, we received patient living with HIV (PLWHA) for CD4 counts, HIV-1 viral load, and/or genotyping of HIV-1 mutation drug resistance. We used the BD FACSPresto for CD4 count, the Biocentric Generic HIV viral load test for HIV-1 quantification, and the HIV-1 drug resistance mutation genotyping (ARNS protocol). Results: A total of 1129 HIV-1 patients have been enrolled for this study. The median age was 46 years old and the median of CD4 was 386 cells per cubic millimeter. The virological suppression success was observed at 62.7% of patients on the former first line regimen and 70.6% of the patient on DBR. We successfully amplified and analyzed 76 sequences and noticed the presence of the nineteen different subtypes with the predominance of the subtypes CRF02-AG (37.95%), followed by subtype A (22.3%). For HIV drug resistance analyses, 108 (65.1%) had resistance mutation to nucleoside reverse transcriptase inhibitors (NRTIs);of these, 91 (84%) present M184V/I. When looking for NNRTI mutations, 119 (71.7%) sequences had at least one mutation. Of these, 82 had K103N (68.9%), representing the main NNRTI mutations. The pattern showing the high level of resistance (HLR) in all molecules of NRTIs and NNRTIs, except for the TDF (intermediate resistance) was M41L-E44DL74I-M184-L210W-T215Y-K101P-K103N-V106I. Conclusion: This report paints a picture of a relatively female-dominated HIV-infected Gabonese population with a low level of immunity. The level of drug resistance with the former first-line regimen suggests the need to monitor the drug Dolutegravir resistance.

Efficacy and safety profiles of dolutegravir plus lamivudine vs.bictegravir/emtricitabine/tenofovir alafenamide in therapy-naïve adults with HIV-1

Background:Dual regimen dolutegravir(DTG)plus lamivudine(3TC)has demonstrated non-inferior efficacy compared to DTG-based three-drug regimens(3DRs),yet directly comparative data regarding the efficacy and safety of DTG+3TC and bictegravir/emtricitabine/tenofovir alafenamide(B/F/TAF)for therapy-naïve people with human immunodeficiency virus(HIV)-1(PWH)are still limited.We aimed to assess the antiviral potency and safety profiles of DTG+3TC vs.B/F/TAF based on antiretroviral therapy(ART)-naïve PWH in China.Methods:This retrospective multicenter study enrolled PWH initiating ART with DTG+3TC or B/F/TAF from 2020 to 2022 in Guangdong and Guangxi.We analyzed response rates based on target not detected(TND)status using intention-to-treat(ITT)analysis.Subgroups were formed based on baseline viral load(VL)(<100,000 vs.≥100,000 copies/mL)and CD4^(+)cell count(<200 vs.≥200 cell/µL).Median time to TND VL was assessed by Kaplan-Meier method.We also measured changes from baseline in CD4^(+)cell counts,CD4/CD8 ratio,lipid parameters,weight,creatinine(Cr),estimated glomerular filtration rate(eGFR),and drug-related adverse effects(DRAEs).Results:We enrolled 280 participants,including 137(48.9%)on DTG+3TC and 143(51.1%)on B/F/TAF.At week 48,96.4%(132/137)on DTG+3TC and 100%(143/143)on B/F/TAF achieved TND(P=0.064).At week 12,TND responses were higher with B/F/TAF(78.3%[112/143])than DTG+3TC(30.7%[42/137])(P<0.001).This trend held across subgroups.B/F/TAF achieved TND faster(12 weeks)than DTG+3TC(24 weeks)(P<0.001).No differences were seen in CD4^(+)cell count and CD4/CD8 ratio,except in the high-VL subgroup,where B/F/TAF showed better recovery.DRAEs were significantly lower with B/F/TAF(4.9%[7/143])than with DTG+3TC(13.1%[18/137])(P=0.016).Lipid parameters,body weight,and Cr increased in both groups over 48 weeks,with DTG+3TC showing a more favorable effect on triglycerides,high-density lipoprotein(HDL)cholesterol,and weight gain.Conclusions:In this real-life study,B/F/TAF led to a faster viral decline and fewer DRAEs compared to DTG+3TC.No significant difference was observed in the TND rate at week 48,regardless of baseline VL and CD4^(+)cell count.CD4^(+)recovery was superior for B/F/TAF in participants with high VL.The DTG+3TC regimen had less impact on metabolic changes than B/F/TAF.

Continuous synthesis of dolutegravir sodium crystals using liquid-gas heterogeneous microreactor

In this work, a liquid-gas heterogeneous microreactor was developed for investigating continuous crystallization of dolutegravir sodium(DTG), as well as revealing reaction kinetics and mixing mechanism with 3-min data acquisition. The reaction kinetics models were established by visually recording the concentration variation of reactants over time in the microchannel via adding pH-sensitive fluorescent dye. The mixing intensification mechanism of liquid-gas flow was quantified through the fluorescent signal to indicate mixing process, demonstrating an outstanding mixing performance with a mixing time less than 0.1 s. Compared with batch crystallization, continuous synthesis of dolutegravir sodium using liquid-gas heterogenous microreactor optimizes crystal distribution size, and successfully modifies the crystal morphology in needle-like habit instead of rod-like habit. The microreactor continuous crystallization can run for 5 h without crystal blockage and achieve D90 of DTG less than 30 μm. This work provides a feasible approach for continuously synthesizing dolutegravir sodium, and can optimize the existing pharmaceutical crystallization.

人类免疫缺陷病毒感染/艾滋病经治患者转换为多替拉韦/拉米夫定复方单片制剂的真实世界研究

目的评估真实世界中达到病毒抑制的人类免疫缺陷病毒(human immunodeficiency virus,HIV)感染/艾滋病(acquired immunodeficiency syndrome,AIDS)患者转换为多替拉韦/拉米夫定(dolutegravir/lamivudine,DTG/3TC)复方单片制剂的疗效及安全性。方法纳入2021年6月1日至2022年6月1日在郑州市第六人民医院门诊长期随访的HIV得到有效抑制并在研究期间抗病毒方案转换为DTG/3TC方案的HIV/AIDS患者79例,收集转换治疗方案前及治疗期间T淋巴细胞亚群、HIV RNA、血脂水平以及肾功能等检测指标,记录不良事件的发生情况。结果79例转换治疗方案患者以中年男性为主,有30.4%的患者合并非艾滋病定义性疾病。前3位转换治疗方案原因分别是:简化方案,改善耐受性、药物不良反应、合并非艾滋病定义性疾病。48周病毒持续抑制率为100%,CD4~+T淋巴细胞计数较基线变化差异无统计学意义(P>0.05);转换治疗方案48周后高密度脂蛋白、血肌酐、血糖、体质量升高,肾小球滤过率和尿微量白蛋白水平下降,差异均有统计学意义(P均<0.05)。有5例患者因血脂异常转换为DTG/3TC方案,转换治疗方案48周后总胆固醇明显下降(P<0.05)。有13例患者因肾毒性转换为DTG/3TC方案,转换治疗方案48周后血肌酐、肾小球滤过率、尿微量白蛋白的变化差异无统计学意义(P均>0.05)。结论达到病毒抑制的患者转换为DTG/3TC方案后能持续抑制病毒、安全性及耐受性好,特别是对于合并非艾滋病定义性疾病、出现肾毒性及血脂异常的患者,DTG/3TC方案是很好的优化治疗方案选择之一。

新一代整合酶抑制剂Dolutegravir的临床应用进展

2007年10月,美国食品药品管理局(USFDA)批准了第一个整合酶抑制剂Raltegravir(Isentress)与其他抗病毒药物联合使用,用于治疗艾滋病病毒(HIV)感染的经治成人病人。Dolutegravir作为新近研发的新一代整合酶抑制剂,目前处于临床III期试验阶段。近期研究结果显示其抗病毒治疗疗效良好,具有耐受性好、低药物相互作用以及独特的耐药特点。2013年2月,美国FDA宣布将加快对该药的审批过程。

多替阿巴拉米片治疗HIV感染的短期疗效及不良反应分析

目的 分析多替阿巴拉米片(商品名:绥美凯)治疗人类免疫缺陷病毒(HIV)感染患者的疗效与药物不良反应发生情况,指导其临床使用。方法 回顾性分析69例明确诊断为HIV感染初始采用多替阿巴拉米片进行抗逆转录病毒治疗(ART)患者的临床资料,观察患者治疗2、4、12周时的临床疗效与不良反应发生情况。结果 69例患者治疗4周时的人类免疫缺陷病毒核糖核酸(HIV-RNA)由治疗前的(5.34±1.13)×log10 IU/ml明显下降至(1.88±0.76)×log10 IU/ml,差异具有统计学意义(P<0.05);患者治疗12周时的HIV-RNA下降至(1.75±0.76)×log10 IU/ml,与治疗前比较差异具有统计学意义(P<0.05)。治疗4周时, 64例(92.8%)患者HIV-RNA<200拷贝/ml。患者治疗4周时的CD+T淋巴细胞计数上升至118.0(86.0, 238.0)个/μl,治疗12周时上升至172.0(89.5, 287.0)个/μl,与治疗前的66.5(19.0, 204.0)个/μl比较差异均有统计学意义(P<0.05);患者治疗12周时的CD+T淋巴细胞计数高于治疗4周时,差异具有统计学意义(P<0.05)。与治疗前、治疗4周时比较,患者治疗12周时CD4/CD8明显升高,差异具有统计学意义(P<0.05)。患者治疗4周时肝功能异常发生率8.7%较治疗前的26.1%明显降低,差异有统计学意义(P<0.05)。患者治疗2、4、12周时肌酐(Cr)水平均高于治疗前,差异有统计学意义(P<0.05);患者治疗2周后Cr水平逐渐回落,治疗2、4、12周时Cr水平比较无明显差异(P>0.05)。患者治疗2、4、12周时甘油三酯(TG)、总胆固醇(TC)水平均高于治疗前,高密度脂蛋白胆固醇(HDL-C)水平高于治疗前,差异具有统计学意义(P<0.05)。结论 多替阿巴拉米片具有高效抑制HIV病毒复制、快速提升免疫应答的特点,用药早期观察到Cr水平升高,但随着时间延长,逐渐回落;同时观察到随着用药时间延长,TC水平趋于上升。

多替拉韦钠系列开环物质的合成

本文报道了两个多替拉韦钠开环杂质合成的新方法。以甲基多替拉韦(多替拉韦钠中间体)为起始原料,在溴化钠催化条件下,使用三甲基氯硅烷进行开环,再经氯化镁脱甲基得到多替拉韦钠开环杂质。所合成的杂质都经过核磁和质谱的表征。该方法可快速、高效地制备出多替拉韦钠开环杂质及其衍生杂质,为多替拉韦钠中间体和原料药的质量研究提供技术支持。

超高效液相色谱-串联质谱法同时测定5种抗逆转录病毒药物血药浓度

目的建立超高效液相色谱-串联质谱(UPLC-MS/MS)法同时测定人血浆中多替拉韦、拉替拉韦、依非韦伦、拉米夫定和替诺福韦浓度,并应用于治疗药物监测。方法分别以多替拉韦-D5、拉替拉韦-D4、依非韦伦-D5、拉米夫定-^(13)C-^(15)N_(2)、替诺福韦-D7作为内标,样本经乙腈沉淀蛋白法处理后稀释进样分析。色谱柱为Shim-pack XR-ODSⅢ(2.0 mm×50 mm,1.6μm),流动相为0.1%甲酸-0.1%甲酸乙腈,梯度洗脱,流速为0.3 mL·min^(-1),柱温40℃。采用电喷雾离子源,正离子-多反应监测模式扫描分析,待方法学验证后用于人类免疫缺陷病毒(HIV)感染患者治疗药物监测。结果多替拉韦、拉替拉韦、依非韦伦、拉米夫定、替诺福韦血药浓度分别在62.5~3000、10~500、125~6000、10~500、10~500 ng·mL^(-1)范围内线性关系良好,线性相关系数(R^(2))均>0.998;四水平质控样品的日内和日间精密度RSD<7%,准确度为94.0%~109.3%;提取回收率为98.7%~104.5%、不同类型血浆基质效应为95.7%~106.0%,且血浆样本在一定的储存环境中稳定性良好。临床样本检测结果显示接受多替拉韦、依非韦伦、拉米夫定、替诺福韦的HIV患者血药谷浓度分别为107.7~2366.0、740.0~3410.0、38.5~1229.3、31.6~224.4 ng·mL^(-1)。结论该方法准确度高、操作简便、成本低,适用于HIV患者多替拉韦、拉替拉韦、依非韦伦、拉米夫定、替诺福韦的治疗药物监测。

抗艾滋病药Dolutegravir

将自身基因整合到宿主细胞染色质中，是包括人类免疫缺陷病毒（HIV）在内的逆转录病毒复制过程中的一个关键步骤，由病毒整合酶介导。因此，整合酶可作为阻断HIV复制的合适靶标，由美国Shionogi．viiVHeahhcare公司开发的dolutegravir（代号：S／GSK．1349572）即为一种口服有效的整合酶抑制剂，其抗HIV活性显著。临床研究显示，对整合酶抑制剂rahegravir产生耐药性的HIV感染者可对本品应答。

含多替拉韦与含依非韦伦方案抗逆转录治疗对人类免疫缺陷病毒感染母婴影响的荟萃分析

目的:分析含多替拉韦方案对比含依非韦伦方案抗逆转录治疗对人类免疫缺陷病毒(HIV)感染母婴影响情况。方法:检索建库至2023年6月在PubMed、EMBase、the Cochrane Library、Medline、中国知网、万方、维普、中国生物医学文献数据库公开发表的中英文研究,采用纽卡斯尔-渥太华量表(NOS)评分方法,纳入符合条件的文献,提取相关数据资料,利用RevMan 5.4软件进行荟萃分析。结果:最终共纳入文献6篇,其中多替拉韦组2769例患者,依非韦伦组6006例患者。两组孕产妇抗逆转录治疗后病毒应答率比较差异有统计学意义(RR=1.25,95%CI 1.06~1.46,Z=2.73,P<0.05)。胎儿及新生儿情况分析中,两组新生儿出生体质量比较差异有统计学意义(MD=0.14,95%CI 0.05~0.22,Z=3.03,P<0.05),而在胎儿及新生儿严重不良事件胎儿宫内死亡(OR=1.08,95%CI 0.78~1.49,Z=0.47,P>0.05)、早产(RR=0.95,95%CI 0.85~1.07,Z=0.82,P>0.05)、新生儿死亡(OR=0.71,95%CI 0.25~2.00,Z=0.65,P>0.05)比较差异无统计学意义。结论:孕期使用含多替拉韦抗逆转录治疗方案的病毒应答率高于含依非韦伦治疗组,同时依非韦伦治疗组新生儿体质量低于含多替拉韦组。

多替拉韦自微乳化释药系统的制备与大鼠药动学评价

目的制备多替拉韦自微乳化释药系统(DTG-SMEDDSs),并对其在大鼠体内的药动学行为进行评价。方法2021年6月至2023年3月通过测定多替拉韦(DTG)在不同种类油、乳化剂和助乳化剂中的平衡溶解度、辅料配伍相容性实验来确定DTG-SMEDDSs的处方组成,根据伪三元相图初步确定各辅料的用量范围,评价DTG-SMEDDSs的热力学稳定性以及在不同稀释倍速中的稳定性,通过透射电镜观察到DTG-SMEDDSs形成乳液的微观形态,考察DTG-SMEDDSs的体外药物溶出速率,通过大鼠口服给药比较DTG混悬剂与DTG-SMEDDSs的大鼠体内药动学特征。结果平衡溶解度和辅料配伍相容性实验确定选择单亚油酸甘油酯(Maisine)作为油相,吐温80作为乳化剂,二乙二醇单乙基醚(Transcutol HP)作为助乳化剂,其配比为30∶35∶35,制备的DTG-SMEDDSs具有良好的热力学稳定性及稀释稳定性,其自乳化形成的微乳呈类球形;DTG-SMEDDSs中的药物在10 min内基本完全溶出,其溶出速率显著快于DTG原料药;大鼠体内药动学结果显示,大鼠口服DTG-SMEDDSs后的达峰浓度(Cmax)是DTG混悬剂的2.46倍,血药浓度-时间曲线下面积(AUC(0-∞))是DTG混悬剂液的2.52倍,说明DTG-SMEDDSs可显著提高药物的达峰浓度,增加药物口服生物利用度。结论多替拉韦自微乳化释药系统,有助于药物快速溶出,显著提高了多替拉韦的口服生物利用度。