Efficacy of dolutegravir + lamivudine q.d. with food in people with TB/HIV using a rifampicin-based regimen: A retrospective observational case series.

OBJECTIVES: Dolutegravir + lamivudine (DTG + 3TC) is a first-line regimen for people with HIV. However, there are still concerns about its efficacy in people with tuberculosis (TB)/HIV due to the lack of available evidence and drug-drug interaction with rifampicin. METHODS: A single-centre retrospective observational case series was conducted in Guangxi Zhuang Autonomous Region, China. We included all people with TB/HIV on combined use of once-daily (q.d.) dosing DTG + 3TC and rifampicin (RIF)-containing anti-TB regimens between 2020 and 2022. HIV-RNA, CD4 cell counts were collected and analysed. RESULTS: In all, 21 people with HIV (PWH) were included in this study. All the PWH were treatment-naïve and told to take DTG + 3TC q.d. with food. The median age was 53 years, and 71.43% were male. A total of 71.43% PWH had baseline viral load (VL) > 100 000 copies/mL, and 33.33% had baseline VL greater than 500 000 copies/mL. Only one PWH had CD4 cell count greater than 200 cells/µL, and the median CD4 count was 20 cells/µL. A total of 16 PWH started DTG + 3TC after initiation of the RIF-based anti-TB regimen, and the other five PWH initiated DTG + 3TC before the treatment of TB. All the PWH had at least 24 weeks of follow-up visits and all of the TB treatments were successful. A total of 20 PWH (95.24%) achieved viral suppression (VL <50 copies/mL). All detected viral loads between weeks 24 and 48 were less than 200 copies/mL. Among the PWH who started DTG + 3TC after the initiation of RIF-based anti-TB regimen, all achieved viral suppression by week 24 except the non-suppressed PWH. CD4 counts were greatly improved after antiretroviral treatment: the median CD4 counts were raised from 20 to 171 cells/µL at week 48. No serious adverse events were reported. CONCLUSIONS: This case series preliminarily validates the efficacy of DTG + 3TC q.d. with food when combined with RIF-based anti-TB regimens in people with TB/HIV.

Prediction of the risk of cytopenia in hospitalized HIV/AIDS patients using machine learning methods based on electronic medical records.

Background: Cytopenia is a frequent complication among HIV-infected patients who require hospitalization. It can have a negative impact on the treatment outcomes for these patients. However, by leveraging machine learning techniques and electronic medical records, a predictive model can be developed to evaluate the risk of cytopenia during hospitalization in HIV patients. Such a model is crucial for designing a more individualized and evidence-based treatment strategy for HIV patients. Method: The present study was conducted on HIV patients who were admitted to Guangxi Chest Hospital between June 2016 and October 2021. We extracted a total of 66 clinical features from the electronic medical records and employed them to train five machine learning prediction models (artificial neural network [ANN], adaptive boosting [AdaBoost], k-nearest neighbour [KNN] and support vector machine [SVM], decision tree [DT]). The models were tested using 20% of the data. The performance of the models was evaluated using indicators such as the area under the receiver operating characteristic curve (AUC). The best predictive models were interpreted using the shapley additive explanation (SHAP). Result: The ANN models have better predictive power. According to the SHAP interpretation of the ANN model, hypoproteinemia and cancer were the most important predictive features of cytopenia in HIV hospitalized patients. Meanwhile, the lower hemoglobin-to-RDW ratio (HGB/RDW), low-density lipoprotein cholesterol (LDL-C) levels, CD4+ T cell counts, and creatinine clearance (Ccr) levels increase the risk of cytopenia in HIV hospitalized patients. Conclusion: The present study constructed a risk prediction model for cytopenia in HIV patients during hospitalization with machine learning and electronic medical record information. The prediction model is important for the rational management of HIV hospitalized patients and the personalized treatment plan setting.

Immune characteristics of human immunodeficiency virus/severe acute respiratory syndrome coronavirus 2 coinfection: A case report and mini-review.

Since its first appearance in Wuhan, China, severe acute respiratory syndrome coronavirus 2 has rapidly spread throughout the world and has become a global pandemic. It remains unclear whether people living with human immunodeficiency virus are at an increased risk of coronavirus disease 2019 and severe disease manifestation; until now, the evidence regarding the outcomes from severe acute respiratory syndrome coronavirus 2 infection in people living with human immunodeficiency virus is still limited and conflicting. The clinical characteristics of seven patients of family cluster-onset coronavirus disease 2019 were reported, including the immune characteristics of one patient of human immunodeficiency virus/severe acute respiratory syndrome coronavirus 2 coinfection. In the patients of human immunodeficiency virus/severe acute respiratory syndrome coronavirus 2 coinfection, about 2 weeks after infection, it was observed that CD4 and CD8 count showed a downward trend and that of CD8 is more obvious; at the same time, lymphocytes showed a slight increase. CD4, CD8, and lymphocytes are in the plateau period from the second week to the fourth week. About 4 weeks after infection, all showed an increase, in which anti-coronavirus combined with antiviral therapy were given. The time for Nucleic Acid Testing to present as negative was 51 days. The other six patients in the family were non-human immunodeficiency virus infected, the familial cluster received parallel treatment, and the median time for the Nucleic Acid Testing to present as negative was 29 days. The patient of human immunodeficiency virus/severe acute respiratory syndrome coronavirus 2 coinfection presents an immune state of CD4's and CD8's dual lymphatic depletion. Human immunodeficiency virus should still be regarded as an important factor in future risk stratification models for coronavirus disease 2019.

Synthesis and characterization of tumor-targeted copolymer nanocarrier modified by transferrin.

To increase the encapsulation of hydrophilic antitumor agent daunorubicin (DNR) and multidrug resistance reversal agent tetrandrine (Tet) in the drug delivery system of nano-particles (NPs), a functional copolymer NP composed of poly(lactic-co-glycolic acid) (PLGA), poly-L-lysine (PLL), and polyethylene glycol (PEG) was synthesized and then loaded with DNR and Tet simultaneously to construct DNR/Tet-PLGA-PLL-PEG-NPs using a modified double-emulsion solvent evaporation/diffusion method. And to increase the targeted antitumor effect, DNR/Tet-PLGA-PLL-PEG-NPs were further modified with transferrin (Tf) due to its specific binding to Tf receptors (TfR), which is highly expressed on the surface of tumor cells. In this study, the influence of the diversity of formulation parameters was investigated systematically, such as drug loading, mean particle size, molecular weight, the concentration of PLGA-PLL-PEG-Tf, volume ratio of acetone to dichloromethane, the concentration of polyvinyl alcohol (PVA) in the external aqueous phase, the volume ratio of the internal aqueous phase to the external aqueous phase, and the type of surfactants in the internal aqueous phase. Meanwhile, its possible effect on cell viability was evaluated. Our results showed that the regular spherical DNR/Tet-PLGA-PLL-PEG-Tf-NPs with a smooth surface, a relatively low polydispersity index, and a diameter of 213.0±12.0 nm could be produced. The encapsulation efficiency was 70.23%±1.91% for DNR and 86.5%±0.70% for Tet, the moderate drug loading was 3.63%±0.15% for DNR and 4.27%±0.13% for Tet. Notably, the accumulated release of DNR and Tet could be sustained over 1 week, and the Tf content was 2.18%±0.04%. In cell viability tests, DNR/Tet-PLGA-PLL-PEG-Tf-NPs could inhibit the proliferation of K562/ADR cells in a dose-dependent manner, and the half maximal inhibitory concentration value (total drug) of DNR/Tet-PLGA-PLL-PEG-Tf-NPs was lower than that of DNR, a mixture of DNR and Tet, and DNR/Tet-PLGA-PLL-PEG-NPs. These results clearly indicate that the PLGA-PLL-PEG formulation is a potential drug delivery system for hydrophilic and hydrophobic drugs, and that Tf modification may increase its targeting properties.

Efficacy and biological safety of lopinavir/ritonavir based anti-retroviral therapy in HIV-1-infected patients: a meta-analysis of randomized controlled trials.

Lopinavir/ritonavir (LPV/r) is the first ritonavir-boosted protease-inhibitor used in second-line anti-retroviral treatment (ART) in resource-limited regions. To evaluate the efficacy and safety outcomes of LPV/r in treatment-naïve and -experienced HIV-infected adults and pregnant women, we performed a meta-analysis of randomized controlled trials. Ten cohorts from 8 articles involving 2,584 ART-naïve patients, 5 cohorts from 4 articles involving 1,124 ART-experienced patients, and 8 cohorts from 7 articles involving 2,191 pregnant women were selected for the meta-analyses. For ART-naïve patients, the virologic response rate (72.3%) of LPV/r combined with tenofovir (TDF) plus lamivudine/emtricitabine (3TC/FTC) arms was significantly greater than that of LPV/r plus non-TDF-FTC arms (65.5%, p = 0.047). For ART-experienced patients, the use of LPV/r revealed a 55.7% probability of virologic success. The incidence of abnormal total cholesterol (6.9%) for ART-experienced patients was significantly lower than that for ART-naïve patients (13.1%, p < 0.001). The use of LPV/r in pregnant women revealed a mother-to-child transmission (MTCT) rate of 1.1%, preterm birth rate of 13.2%, and low birth weight rate of 16.2%. Our meta-analysis indicated that LPV/r was an efficacious regimen for ART-naïve patients and was more tolerable for ART-experienced patients. LPV/r also displayed a significant effect in preventing MTCT.

Study on the release of fenofibrate nanosuspension in vitro and its correlation with in situ intestinal and in vivo absorption kinetics in rats.

As an oral delivery carrier for poorly water soluble drugs, the nanosuspension was prepared by melt emulsification method combined with high-pressure homogenization. The objective of this study was to clarify the absorption mechanism in rats of fenofibrate nanosuspension using the model of in situ gut perfusion. The release rate of drug from nanosuspension was fast which about 70% of the drug would be released within 5 minutes. The absorption of fenofibrate nanosuspension in the gastrointestinal (GI) tract was studied by the in situ closed loop method in rats. It was found that the absorption process in intestine was first-process with passive diffusion mechanism, and the whole intestine was the major segment for the drug absorption. Additionally, GI absorption in situ studies indicated that the fenofibrate nanosuspension had great success in regard to enhancement of intestinal absorption compared to the fenofibrate suspension of coarse powder. The pharmacokinetic characteristics were studied in rats after oral administration of fenofibrate nanosuspension or suspension at the dosage of 27 mg/kg. The plasma concentration-time curve was fitted to the one-compartment model. The correlation between in vitro dissolution (P), in situ intestinal absorption (F) and in vivo absorption (Fa) in rats was investigated with the results as follows: Fa = 6.2061P-456.38(r = 0.9559), F = 3.6911P-2.2169(r = 0.970), F = 0.5095P + 44.189(r = 0.9609). The highest level A could be obtained from the in vitro--in vivo correlation (IVIVC) between dissolution percentage and intestinal absorption of the fenofibrate nanosuspension in rats. Consequently, the in situ intestinal perfusion model could be used to predict the in vivo pharmacokinetic characteristics in rats.

Dissolution improvement of poorly water-soluble drug by cogrinding method using jar mill.

As a representative proton pump inhibitor, Lansoprazole was poorly soluble in water which caused the low oral bioavailability. The present study was carried out to enhance the dissolution of lansoprazole by cogrinding with some commonly used hydrophilic polymers (ß-CD, PVP, HPMC, L-HPC, CS, PEG and PVPP) in the weight ratio of 1:1 for 2 h in the jar mill. Samples of coground mixture, micronised drug, and physical mixture were characterized by XRPD, and DSC, the results showed that the drug crystallinity reduced in the coground process. The amount of drug released from the coground mixtures in PBS (pH 6.8, 37°C) in 30 min was 100% approximately (except the coground mixtures prepared with VPP or PEG) while released from the micronised drug was just about 20%. Increasing the hydrophilicity and diminishing the size of drug particles by cogrinding were the main causes for enhancing the dissolution of the drug. The results of the stability study of lansoprazole in coground mixture showed that there were no significant changes in the drug content and dissolution characteristics 6 months later. It is clear that the cogrinding method described in the article is very effective for enhancing the dissolution of the poorly soluble drugs, and it is easy for industrialization, showing a strong potential for future applications.

Formulation and pharmacokinetic evaluation of a paclitaxel nanosuspension for intravenous delivery.

Paclitaxel is a diterpenoid isolated from Taxus brevifolia. It is effective for various cancers, especially ovarian and breast cancer. Due to its aqueous insolubility, it is administered dissolved in ethanol and Cremophor EL (BASF, Ludwigshafen, Germany), which can cause serious allergic reactions. In order to eliminate Cremophor EL, paclitaxel was formulated as a nanosuspension by high-pressure homogenization. The nanosuspension was lyophilized to obtain the dry paclitaxel nanoparticles (average size, 214.4 ± 15.03 nm), which enhanced both the physical and chemical stability of paclitaxel nanoparticles. Paclitaxel dissolution was also enhanced by the nanosuspension. Differential scanning calorimetry showed that the crystallinity of paclitaxel was preserved during the high-pressure homogenization process. The pharmacokinetics and tissue distribution of paclitaxel were compared after intravenous administration of paclitaxel nanosuspension and paclitaxel injection. In rat plasma, paclitaxel nanosuspension exhibited a significantly (P < 0.01) reduced area under the concentration curve (AUC)(0-∞) (20.343 ± 9.119 µg · h · mL(-1) vs 5.196 ± 1.426 µg · h · mL(-1)), greater clearance (2.050 ± 0.616 L · kg(-1) · h(-1) vs 0.556 ± 0.190 L · kg(-1) · h(-1)), and shorter elimination half-life (5.646 ± 2.941 vs 3.774 ± 1.352 hours) compared with the paclitaxel solution. In contrast, the paclitaxel nanosuspension resulted in a significantly greater AUC(0-∞) in liver, lung, and spleen (all P < 0.01), but not in heart or kidney.

Preparation of fenofibrate nanosuspension and study of its pharmacokinetic behavior in rats.

BACKGROUND: In this study, nanosuspension was prepared to improve the dissolution rate and bioavailability of lipophilic fenofibrate. METHOD: Melt emulsification method combined with high-pressure homogenization was adapted, and mixture of poloxamer188 and PVP K30 were selected as surfactants. This method consumed less energy and was more efficient than traditional homogenization of drug solid particles suspension directly. RESULTS: The dissolution rate of fenofibrate nanosuspension was increased obviously, and the product was evaluated by pharmacokinetic characteristic in rats. The AUC(0-36 h) and C(max) of nanosuspensions were increased when compared with the reference formulations. No significant differences were found between the two nanosuspensions A and B, of which the mean particle sizes were 356 and 194 nm, respectively. Therefore, nanosuspensions may be a suitable delivery system to improve the bioavailability of those drugs with poor water solubility.

Targeted delivery of doxorubicin using stealth liposomes modified with transferrin.

Site-specific delivery of drugs and therapeutics can significantly reduce drug toxicity and increase the therapeutic effect. Transferrin (Tf) is one suitable ligand to be conjugated to drug delivery systems to achieve site-specific targeting, due to its specific binding to transferrin receptors (TfR), highly expressed on the surfaces of tumor cells. Stealth liposomes are effective vehicles for drugs, genes and vaccines and can be easily modified with proteins, antibodies, and other appropriate ligands, resulting in attractive formulations for targeted drug delivery. In this study, we prepared doxorubicin-loaded stealth liposomes (Tf-SL-DOX) by film dispersion followed by ammonium sulphate gradient method, then conjugated Tf to the liposome surface by an amide bound between DSPE-PEG(2000)-COOH and Tf. The results of the intracellular uptake study indicated that Tf-modified SL was able to enhance the intracellular uptake of the entrapped DOX by HepG2 cells compared to SL-DOX. We studied tissue distribution and therapeutic effects of Free DOX, SL-DOX and Tf-SL-DOX in tumor-bearing mice and pharmacokinetics in rats. The pharmacokinetic behavior of Tf-SL-DOX in the plasma was closed to SL-DOX. Administration of Tf-SL-DOX to tumor-bearing mice could be used to deliver DOX effectively to the targeted site, significantly increasing DOX concentration in tumor and decreasing DOX concentration in heart and kidney. In summary, our study indicated that the Tf-coupled PEG liposomes (Tf-SL) could be as the targeted carriers to facilitate the delivery of the encapsulated anticancer drugs into tumor cells by receptor-mediated way.

PLGA nanoparticles for the oral delivery of 5-Fluorouracil using high pressure homogenization-emulsification as the preparation method and in vitro/in vivo studies.

The objective of the present study was to incorporate the hydrophilic anti-cancer drug 5-Fluorouracil(5-FU) into poly(lactide-co-glycolide) (PLGA) nanoparticles(NP) to improve the oral bioavailability. Owing to the high solubility of 5-FU in basic water, the water-in-oil-in-water (w/o/w) emulsification process has been chosen as one of the most appropriate method for the encapsulation of 5-FU, and the ammonia solution was used as the inner aqueous phase solvent to increase the solubility of 5-FU. In order to reach submicron size as well as increasing the grade of monodispersity compared to previous preparation techniques, we prepared 5-FU loaded PLGA-NP by a high-pressure emulsification-solvent evaporation process. The PLGA-NPs were characterized with respect to their morphology, particle size, size distribution, 5-FU encapsulation efficiency, in vitro and in vivo studies in rats. In vitro release of 5-FU from nanoparticles appeared to have two components with an initial rapid release due to the surface associated drug and followed by a slower exponential release of 5-FU, which was dissolved in the core. The in vivo research was studied in male Sprague-Dawley rats after an oral 5-FU dose of 45 mg/kg. Single oral administration of 5-FU loaded PLGA-NP to rats produced bioavailability, which was statistically higher than 5-FU solution as negative control. And the MRT (mean residence time) of 5-FU loaded PLGA-NP was significantly (P < 0.05) modified. Thus, it is possible to design a controlled drug delivery system for oral 5-FU delivery, improving therapy efficiency by possible reduction of time intervals between peroral administrations and reduction of local gastrointestinal side effects.