Treatment Of HIV-infected Patients Research Articles

Efficacy and safety of Ibalizumab for the treatment of HIV-1 infected patients: A systematic review

Objectives: Human immunodeficiency virus (HIV) infection is a significant global health concern, due to the emerging complexity in the management of infection. The emergence of novel therapeutic agents, such as ibalizumab, has provided a ray of hope for individuals living with HIV. This systematic review provides a comprehensive analysis of the efficacy and safety of ibalizumab for the treatment of HIV-1-infected patients. Material and Methods: Using online medical literature databases and the preferred reporting items for systematic reviews and meta-analysis (PRISMA) guidelines, four of the 86 articles met the acceptance criteria to be analyzed. Details such as author name, year of publication, demographic characteristics, mode, and dose of drug administration, duration of treatment, comparator if any, baseline CD4 counts, and viral load, change in CD4 count and viral load, and the adverse events were noted in the studies. Results: The total number of patients enrolled in each study ranged from 22 to 82 with a median age ranging from 39 to 53. Except for the open-label dose-ranging cohort study, baseline CD4 counts and post-intervention CD4 counts were assessed in all the studies. The patients who received a higher dose of ibalizumab showed an early significant rise in CD4+T-cell count at week 16 and week 48. Although the viral reduction after ibalizumab injection increases from the dose of 3 mg/kg, it was noted that beyond 10mg/kg the viral load reduction was not increasing proportionately with 25 mg/kg. The adverse effects encountered among the four studies ranged from 45% to 91%. The commonly observed adverse effects were headache, diarrhea, nausea, fatigue, somnolence, and rash. Conclusion: Ibalizumab demonstrates promise as a therapeutic option for individuals with multidrug-resistant HIV-1. Its unique mechanism of action and positive impact on viral load reduction and CD4 cell counts make it a valuable addition to the armamentarium of HIV treatment options.

Prevalence of syphilis in HIV-infected patients with transmission risk and influencing factors in Zhejiang Province

Objective: To investigate the prevalence of syphilis in HIV-infected patients with transmission risk and influencing factors in Zhejiang Province. Method: The information about the HIV-infected patients, who were alive, had been diagnosed with HIV for >1 year, had received no antiviral treatment or had HIV viral load ≥50 copies/ml, and were aged ≥15 years, reported in Zhejiang as of December 31, 2018 were collected from China Information System for Disease Control and Prevention. The information included general demographic characteristics, sexual behavior characteristics and antiretroviral therapy and syphilis serological test results. The prevalence of syphilis and the influencing factors were analyzed by logistic regression model. The SPSS 19.0 software was used for statistical analysis. Results: A total of 2 275 HIV-infected patients were at risk of HIV transmission, and 75.5% (1 717/2 275) of them were tested for syphilis, the prevalence rate of syphilis was 8.7% (150/1 717). Among the HIV-infected patients with syphilis, 11.3% (17/150) received no antiviral treatment, 38.7% (58/150) had viral load of 50-999 copies/ml and 50.0% (75/150) had ≥1 000 copies/ml. Multivariate logistic regression analysis showed that being men (aOR=2.04, 95%CI:1.06-3.96), homosexual transmission (aOR=1.53, 95%CI:1.04-2.27), history of sexually transmitted diseases (STDs) before HIV diagnosis (aOR=1.98, 95%CI:1.35-2.92) and HIV viral load ≥1 000 copies/ml (aOR=1.90, 95%CI:1.09-3.30) were the risk factors for syphilis. Marriage (aOR=0.47, 95%CI: 0.29-0.76) was a protective factor for syphilis. Conclusions: The prevalence of syphilis was high in HIV-infected patients with transmission risk in Zhejiang. It is urgent to carry out classified management and targeted intervention in HIV-infected patients, explore multi-disease prevention and treatment mechanism, strengthen syphilis screening and treatment in HIV-infected patients to reduce the transmission of HIV and syphilis.

Development of an Isothermal Point-of-care Genetic Rapid Test for the Detection of the HLA-B*57:01 Allele, a Predictor for Hypersensitivity Reaction Caused by Abacavir, for Stratifying Patients for Antiretroviral Abacavir HIV Therapy

Background: Abacavir is used in the treatment of HIV-infected patients. A hypersensitive reaction (HSR) occurs in about 5-8% of patients treated with Abacavir. The HLA-B*57:01 allele is a valuable predictor for HSR and its screening is mandatory prior to treatment with Abacavir. Objective: Current screening methods require considerable investments for equipment. In order to lower the required investments and enable physician practices to perform the screening in a point-of-care (PoC) setting, our objective was to develop a novel isothermal genetic rapid test that requires a minimal setup cost, does not require specific training and thus is suitable for a physician practice setting. Methods: We developed an isothermal recombinase polymerase amplification (RPA) for the specific amplification of the HLA-B*57:01 allele using allele-specific primers coupled to Biotin. Primers specific for human lactase gene, coupled to Digoxigenin, were used as an internal amplification control (IAC). Lateral flow dipstick provided rapid and accurate detection of HLA-B*57:01 allele and IAC via the respective antibodies sprayed on the strips surface. Results: The reference method identified the HLA-B*57:01 allele in the reference sample, in 2 out of 28 buccal swab samples and in 2 out of 13 blood samples. The initial isothermal RPA resulted in unspecific amplification of the HLA-B*57:01 allele. By further optimization steps the specific amplification of the allele and the detection on lateral flow dipstick was observed. The newly developed isothermal RPA was validated. Conclusion: The method developed fulfils the requirements for a genetically based PoC screening system for the HLA-B*57:01 variant, requiring a minimal investment for a heating block and a pipette.

Korean Red Ginseng slows coreceptor switch in HIV-1 infected patients

BackgroundHuman immunodeficiency virus-1 (HIV-1) that binds to the coreceptor CCR5 (R5 viruses) can evolve into viruses that bind to the coreceptor CXCR4 (X4 viruses), with high viral replication rates governing this coreceptor switch. Korean Red Ginseng (KRG) treatment of HIV-1 infected patients has been found to slow the depletion of CD4+ T cells. This study assessed whether the KRG-associated slow depletion of CD4+ T cells was associated with coreceptor switching. MethodsThis study included 146 HIV-1-infected patients naïve to antiretroviral therapy (ART) and seven patients receiving ART. A total of 540 blood samples were obtained from these patients over 122 ± 129 months. Their env genes were amplified by nested PCR or RT-PCR and subjected to direct sequencing. Tropism was determined with a 10% false positive rate (FPR) cutoff. ResultsOf the 146 patients naïve to ART, 102 were KRG-naïve, and 44 had been treated with KRG. Evaluation of initial samples showed that coreceptor switch had occurred in 19 patients, later occurring in 38 additional patients. There was a significant correlation between the amount of KRG and FPR. Based on initial samples, the R5 maintenance period was extended 2.35-fold, with the coreceptor switch being delayed 2.42-fold in KRG-treated compared with KRG-naïve patients. The coreceptor switch occurred in 85% of a homogeneous cohort. The proportion of patients who maintained R5 for ≥10 years was significantly higher in long-term slow progressors than in typical progressors. ConclusionKRG therapy extends R5 maintenance period by increasing FPR, thereby slowing the coreceptor switch.

P1077: HODGKIN LYMPHOMA IN PATIENTS WITH HIV: NATIONAL RETROSPECTIVE MULTICENTER STUDY

Background: Patients with HIV infection have a significantly higher risk of developing cancer than the general population. In the era of antiretroviral therapy (ART) the cancer risk and mortality have been decreased, however, the risk of developing Hodgkin lymphoma (HL) increased. The ART allows treating HIV-infected patients with lymphomas with protocols for patients in the general population. Withal the data on the results of the treatment HL in patients with HIV controversy. Aims: To study epidemiology and evaluate the results of the treatment of HL in patients with HIV in national multicenter study. Methods: The study included 45 patients with HL in patients with HIV who received treatment in 9 Russian centers from 2007 to 2021. The median follow-up was 9 months (1-129). Patients and treatment characteristics were analyzed. Overall survival (OS) and progression-free survival (PFS) were calculated within two years from the diagnosis using the Kaplan-Meier method. Results: The median age was 39 years (25-66), men - 25 (55.6%), women - 20 (44.4%). Histological variants of HL in most cases were represented by nodular sclerosis (56%) and mixed-cell variant (41%). The advanced stage of the disease (3-4 Ann Arbor) was observed in 72.7% of patients, B-symptoms at the onset of the disease - 68.2%. The majority of patients (97.7%) received ART at the diagnosis of HL. The median number of CD4+ cells/µl at the onset of HL was 352.8 (50-692) cells/μl. General somatic status at the start of chemotherapy ECOG 0-1 - 34 (82.9%), ECOG≥2 - 7 (17.1%). As the first line of therapy, patients with localized stages of HL received ABVD (75%) and BEACOPP (25%), with advanced stages - ABVD (61.3%) and BEACOPP (38.7%). The median courses of first-line therapy were 4 (1-10). Radiation therapy in first-line therapy was performed in 4 patients (8.9%). The structure of response to first-line therapy were complete response - 51.4%, partial response - 25.7%, disease stabilization - 2.9%, disease progression - 20%. Fourteen and 8 patients received second and third-line therapy, respectively. Autologous hematopoietic stem cell transplantation was performed in 6 patients - the only 42.8% of patients with relapsed / refractory HL. OS in the study group was 81%, PFS - 38% (median PFS - 23 months). The level of CD4+ cells at the onset of HL less than 250/µl was associated with a statistically significant worsening of OS during 1 year (50% vs 100%, p=0.014). Factors such as gender, age, stage of the disease, ECOG status, the presence of B-symptoms at the onset of the disease, and the treatment regimen did not statistically significantly affect the two years OS and PFS from the diagnosis of HL in patients with HIV. Summary/Conclusion: The national multicenter study allowed characterization of HL in patients with HIV and evaluation of the efficacy of first-line therapy, which was found to be lower than in the general population. The level of CD4+ cells was the only factor that affect 2-year OS. The obtained data can form the basis for further prospective studies aimed at improving the results of HL treatment in HIV-infected patients.

Low-level Viremia in Treated HIV-1 Infected Patients: Advances and Challenges

Antiretroviral therapy (ART) can effectively suppress HIV-1 replication, improving quality of life and restoring the lifespan of persons living with HIV (PLWH) to near-normal levels. However, after standardized ART, a low level of HIV-1 RNA, i.e., low-level viremia (LLV), may still be identified in 3% to 10% of the patients. LLV is capable of impacting the immunological and clinical outcomes of patients and serves as a risk factor for transmission. The underlying mechanism of LLV is not yet certain, and the effects of LLV on patient outcomes remain under evaluation. Understanding LLV will allow effective prevention and control strategies to be designed for the benefit of PLWH.

Reduction of CD8 T Cell Functionality but Not Inhibitory Capacity by Integrase Inhibitors

Although HIV-specific CD8 T cells are effective in controlling HIV infection, they fail to clear infection even in the presence of antiretroviral therapy (ART) and cure strategies such as "shock-and-kill." Little is known how ART is contributing to HIV-specific CD8 T cell function and the ability to clear HIV infection. Therefore, we first assessed the cytokine polyfunctionality and proliferation of CD8 T cells from ART-treated HIV+ individuals directly ex vivo and observed a decline in the multifunctional response as well as proliferation indices of these cells in individuals treated with integrase inhibitor (INSTI) based ART regimens compared to both protease inhibitor (PI) and nonnucleoside reverse transcriptase inhibitor (NNRTI) based regimens. We next cocultured CD8 T cells with different drugs individually and were able to observe reduced functional properties with significantly decreased ability of CD8 T cells to express IFN-γ, MIP1β and TNF-α only after treatment with INSTI-based regimens. Furthermore, previously activated and INSTI-treated CD8 T cells demonstrated reduced capacity to express perforin and granzyme B compared to PI and NNRTI treated cells. Unexpectedly, CD8 T cells treated with dolutegravir showed a similar killing ability 7 dpi compared to emtricitabine or rilpivirine treated cells. We next used a live cell imaging assay to determine the migratory capacity of CD8 T cells. Only INSTI-treated cells showed less migratory activity after SDF-1α stimulation compared to NRTI regimens. Our data show that the choice of ART can have a significant impact on CD8 T cell effector functions, but the importance for potential eradication attempts is unknown. IMPORTANCE Integrase Strand Transfer Inhibitors (INSTI) are recommended by national and international guidelines as a key component of ART in the treatment of HIV infected patients. In particular, their efficacy, tolerability and low drug-drug interaction profile have made them to the preferred choice as part of the first-line regimen in treatment-naive individuals. Here, we demonstrate that the choice of ART can have a significant impact on function and metabolism of CD8 T cells. In summary, our study provides first evidence on a significant, negative impact on CD8 T cell effector functions in the presence of two INSTIs, dolutegravir and elvitegravir, which may contribute to the limited success of eradicating HIV-infected cells through "shock-and-kill" strategies. Although our findings are coherent with recent studies highlighting a possible role of dolutegravir in weight gain, further investigations are necessary to fully understand the impact of INSTI-based regimens on the health of the individual during antiretroviral therapy.

Strategy of planning HIV/AIDS fight in Ukraine: a review

HIV epidemic in Ukraine remains a nationwide problem. The current epidemiological situation does not yet give grounds to talk about a significant decrease in the load associated with HIV/AIDS in Ukraine. Predicting the further spread of the epidemic throughout the country is becoming more and more complicated due to the crisis socio-economic phenomena and the deterioration of the situation in the eastern regions of Ukraine.
 Objective — to substantiate the ways of optimization of monitoring, diagnosis and treatment of HIV infection as the basis for a strategy of overcoming the HIV/AIDS epidemic in the public health system in Ukraine; expanding treatment of HIV-infected patients using modern approaches and standards; volumes and algorithms of cooperation of specialists from different branches in the provision of treatment services to patients with skin diseases and sexually transmitted infections.
 Materials and methods. We analyzed: 1) documents of international policy in the field of public health; 2) the latest changes in the documents of the state policy in the field of health care of Ukraine; 3) international strategies and approaches to overcoming the HIV epidemic; 4) WHO strategies for applying public health approaches to tackling the HIV epidemic; 5) the dynamics of the incidence of skin and venereal diseases in Ukraine and the virtual creation of an epidemiological situation in the absence of integrative relations between individual health care services; 6) modeling and forecasting with account of all available relevant data as an important source of information for monitoring national and global HIV epidemics, as well as managing the prevention and treatment programs.
 Results and discussion. Based on the review of statistical information, key directions are presented for further strengthening of the system of monitoring and evaluation to strengthen the control over the HIV epidemic in Ukraine, as well as optimize specific treatment. At the present stage of the implementation of medical reforms, final revision and improvement are required of existing strategies and policies for organizing a response to the HIV epidemic in Ukraine, as well as the search for new ways and tools that can be mobilized in the health care system by increasing the efficiency of the use of existing resources, introducing new forms of management and coordination of actions.
 Conclusions. Bringing national standards in line with the best world practices in the field of HIV counteraction contributes to the effective planning of the need for specific therapy in order to ensure a sustainable response to the HIV epidemic in Ukraine, the use of a «treat all» approach with effective and safe antiretroviral therapy. The optimization is based on the principles of public health as having the highest priority and effectiveness in comparison with individual approaches to the prevention, treatment and support of people with chronic diseases. The principle of maintaining balanced treatment regimens helps to reduce dependence on donor funding in the context of limited resources in Ukraine, as well as ensure the achievement of Fast track goals and adherence to the UNAIDS strategy.

888. In Vitro Forgiveness of INSTI-Containing Regimens at Drug Concentrations Simulating Variable Adherence

BackgroundThe integrase strand transfer inhibitor (INSTI)-based regimens bictegravir/emtricitabine/tenofovir alafenamide (BIC/FTC/TAF), dolutegravir (DTG)+FTC/TAF, DTG/lamivudine (3TC), and DTG/rilpivirine (RPV) are all used for treatment of HIV-infected patients. Here, relative time to in vitro viral breakthrough (VB) and resistance barrier using simulated human drug exposures at either full or suboptimal treatment adherence to each regimen were compared.MethodsWild-type HIV-1 (IIIb)-infected MT-2 cells were exposed to the combinations of BIC+FTC+TAF, DTG+FTC+TAF, DTG+3TC, or DTG+RPV for up to 35 days or until VB. Fixed drug concentrations were the human plasma-free adjusted clinical trough concentrations (Cmin) or fixed at simulated Cmin after missing 1 to 4 consecutive doses (Cmin-1 to -4), with many replicates. Drug resistance was studied by next-generation sequencing at ≥2% frequency.ResultsAt drug concentrations corresponding to full adherence and 1 missed dose (Cmin and Cmin-1), no VB occurred with any regimen (Table). At Cmin-2, only DTG+3TC had VB, with some emergent resistance to both drugs. At Cmin-3, all regimens had VB: by day 12, 100% of DTG+3TC wells had VB; for BIC+FTC+TAF, DTG+FTC+TAF, and DTG+RPV, < 15% of wells had VB which began after day 14. Emergent RT or IN resistance was seen for DTG+RPV and DTG+3TC but not for BIC+FTC+TAF or DTG+FTC+TAF. At Cmin-4, all DTG+3TC and DTG+FTC+TAF wells had VB by day 12, while DTG+RPV had 94% VB by day 25 and BIC+FTC+TAF had 50% VB by day 35. Emergent Cmin-4 drug resistance was seen for all regimens but at differing frequencies; DTG+RPV had the most wells with resistance. Cumulatively, emergent RT and/or IN resistance was found in 1.3% BIC+FTC+TAF, 2.5% DTG+FTC+TAF, 7.9% DTG+3TC, and 8.8% DTG+RPV cultures.Summary of Forgiveness and Barrier to Resistance of INSTI-Containing Regimens ConclusionRegimen forgiveness and resistance barrier are important factors in long term treatment. These INSTI-based regimens had high in vitro forgiveness and resistance barriers with concentrations simulating high adherence. When multiple missed doses were simulated in vitro, BIC+FTC+TAF had the highest forgiveness and barrier to resistance. When compared to DTG+3TC and DTG+FTC+TAF, DTG+RPV had higher forgiveness but lower resistance barrier after several simulated missed doses.Disclosures Rima K. Acosta, BS, Gilead Sciences, Inc. (Employee, Shareholder) Andrew Mulato, BS, MBA, Gilead Sciences, Inc. (Employee, Shareholder) Michelle L. D’Antoni, PhD, Gilead Sciences (Employee, Shareholder)Gilead Sciences, Inc (Employee, Shareholder) Stephen R. Yant, PhD, Gilead Sciences, Inc. (Employee, Shareholder) Tomas Cihlar, PhD, Gilead Sciences, Inc. (Employee, Shareholder) Kirsten L. White, PhD, Gilead Sciences, Inc (Employee, Shareholder)

Pustular psoriasis and arthropathy in a patient with HIV infection. Clinical case

The article presents a clinical case of pustular psoriasis and arthropathy in a patient with HIV infection. The diagnosis of psoriasis was confirmed by morphological examination. Signs of arthropathy were confirmed by X-Ray: presence of oligoarthritis of the distal interphalangeal joints of the fingers and feet was seen. Dactylitis severity ― 23 points, the Ritchie index ― 2, DLQI ― 28. The clinical course of psoriasis and its treatment in HIV-infected patients was considered after taking into account the data from literature and the patients current condition and observation. The above observation of a combination of several clinical forms of psoriasis (vulgar, pustular and arthropathy) in patients with HIV infection is an illustration of the features of the course and comorbidity of chronic dermatosis and AIDS, due to the influence of the infectious process, immunosuppression and ART. The development of pustular form and arthropathy creates the additional challenge of prescribing basic systemic treatment for severe and complicated psoriasis in an HIV-infected patient due to the presence of contraindications due to comorbidity. The glucocorticosteriod selected by the committee was effective on the skin and joint pathological processes, without having any negative impact on the course and treatment of the HIV infection. Such cases require further study and development of methods for the treatment of patients with comorbidity and their inclusion in an additional section in the clinical recommendations for the diagnosis and treatment of psoriasis.

Extracellular Microvesicles Released From Brain Endothelial Cells are Detected in Animal Models Of HIV-1 Signifying Unresolved Inflammation

Treatment of HIV-infected patients with antiretroviral therapy (ART) has effectively suppressed viral replication; however, the central nervous system is still a major target and reservoir of the virus leading to the possible development of HIV-associated neurocognitive disorders (HAND). Furthermore, a hallmark feature of HAND is the disruption of the blood–brain barrier that leads to loss of tight junction protein (TJP) complexes. Extracellular vesicles (EVs), released by every cell type in the body, occur in greater quantities in response to cellular activation or injury. We have found that inflammatory insults activate brain endothelial cells (EC) and induce the release of EVs containing TJPs such as Occludin. We thus hypothesized that HIV infection and unresolved neuroinflammation will result in the release of brain-EC derived EVs. Herein, our results show elevated levels of brain-EC EVs in a humanized mouse model of HIV infection. Furthermore, while ART reduced brain-EC EVs, it was unable to completely resolve increased vesicles detectable in the blood. In addition to inflammatory insults, HIV-1 viral proteins (Tat and gp120) increased the release of Occludin + vesicles from human brain microvasculature ECs. This increase in vesicle release could be prevented by knock-down of the small GTPase ARF6. ARF6 has been shown to regulate EV biogenesis in other cell types, and we provide further evidence for the involvement of ARF6 in brain EC derived EVs. Overall, this study offers insight into the process of brain vascular remodeling (via EVs) in the setting of neuroinflammation and thus provides possibilities for biomarker monitoring and targeting of ARF6.Graphical abstract

Baseline Xpert MTB/RIF ct values predict sputum conversion during the intensive phase of anti-TB treatment in HIV infected patients in Kampala, Uganda: a retrospective study

BackgroundIn resource-limited settings, sputum smear conversion is used to document treatment response. Many People living with HIV (PLHIV) are smear-negative at baseline. The Xpert MTB/RIF test can indirectly measure bacterial load through cycle threshold (ct) values. This study aimed to determine if baseline Xpert MTB/RIF could predict time to culture negativity in PLHIV with newly diagnosed TB.MethodsA subset of 138 PLHIV from the ‘SOUTH’ study on outcomes related to TB and antiretroviral drug concentrations were included. Bacterial load was estimated by Mycobacterium Growth Indicator Tubes (MGIT) culture time-to-positivity (TTP) and Lowenstein Jensen (LJ) colony counts. Changes in TTP and colony counts were analyzed with Poisson Generalised Estimating Equations (GEE) and multilevel ordered logistic regression models, respectively, while time to culture negativity analysed with Cox proportional hazard models. ROC curves were used to explore the accuracy of the ct value in predicting culture negativity.ResultsA total of 81 patients (58.7%) were males, median age 34 (IQR 29 ̶ 40) years, median CD4 cell count of 180 (IQR 68 ̶ 345) cells/μL and 77.5% were ART naive. The median baseline ct value was 25.1 (IQR 21.0 ̶ 30.1). A unit Increase in the ct value was associated with a 5% (IRR = 1.05 95% CI 1.04 ̶ 1.06) and 3% (IRR = 1.03 95% CI 1.03 ̶ 1.04) increase in TTP at week 2 and 4 respectively. With LJ culture, a patient’s colony grade was reduced by 0.86 times (0R = 0.86 95% CI 0.74 ̶ 0.97) at week 2 and 0.84 times (OR = 0.84 95% CI 0.79 ̶ 0.95 P = 0.002) at week 4 for every unit increase in the baseline ct value. There was a 3% higher likelihood of earlier conversion to negativity for every unit increase in the ct value. A ct cut point ≥28 best predicted culture negativity at week 4 with a sensitivity of 91. 7% & specificity 53.7% while a cut point ≥23 best predicted culture negativity at week 8.ConclusionBaseline Xpert MTB/RIF ct values predict sputum conversion in PLHIV on anti-TB treatment. Surrogate biomarkers for sputum conversion in PLHIV are still a research priority.

Ethical Issues, Discrimination and Social Responsibility Related to HIV-Infected Patients

The aim of the present study was to assess the attitude of students attending 4th and 6th year of the Faculty of Dental Medicine in Iasi towards HIV-seropositive patients. A questionnaire was elaborated, containing 14 ethic statements related to some aspects they may encounter in their future career: the observance of confidentiality and the rights of HIV/AIDS infected patients, the refusal of dedicated treatment and the appreciation of discrimination in this situation. The results have identified some negative aspects regarding the above mentioned issues, mainly in terms of the refusal of specialized treatment. A percentage between 47.4% and 38.4% of the students strongly agreed to the affirmations according to which the risk of cross-infection and the lack of some safety conditions at work may be a reason for the refusal to provide dental treatment. The responses referring to discrimination suggest that there is a negative attitude towards the following aspects: the treatment of HIV-infected patients in different offices, the refusal to continue treatment after confirmation of the diagnosis, the refusal to cooperate with an infected colleague. Only 57.8% of the subjects considered the refusal of treatment as discrimination, with no statistical differences between the years of study. The results suggest both the need to modify the academic curriculum by introducing some ethics and medical legislation courses, and the adoption of a strategy for the increase of empathy and social responsibility in relation to this group of discriminated persons.

PROBLEMS OF DOMESTIC PRODUCTION OF STRATEGICALLY SIGNIFICANT ANTI-RETROVIRAL DRUGS

Purpose. The aim of the study was to assess the problems of providing patients with HIV in the Russian Federation with antiviral drugs of the ATС group – J05AF (nucleosides and nucleotides - reverse transcriptase inhibitors) included in the list of strategically important drugs, and the prospects for its improvement. Materials and methods. The scientific research was carried out sequentially and included four interrelated stages. The objective of the first stage was to analyze the auctions for public procurement of antiretroviral drugs of the ATС- J05AF group for 6 INNs included in the list of strategically important drugs. The task of the second stage of the work was a comparative analysis of the dynamics of the range of antiretroviral drugs and substances for their production, registered in the Russian Federation, of the ATС group - J05AF by 6 INN. At the third stage, an analysis was made of the availability of interchangeable drugs for each INN. The objective of the fourth stage was to analyze the registered prices for domestic and foreign medicines for each INN. Results. It was found that by 2020 the share of domestic drugs was 63% of the planned 90%. In the Russian Federation, only 4 manufacturers in a limited range produce drugs for the treatment of HIV-infected patients. For individual INNs, domestic substances are completely absent, or are produced in insufficient quantities, which forces manufacturers to purchase pharmaceutical substances from the same enterprises, mainly in China and India. In the State Register of Medicines by 2020, for various INNs, interchangeable medicines appeared, the price of which does not differ statistically significantly, nevertheless, 91% of auctions in 2018 were held with a single supplier. Such a result of the auctions is difficult to explain, since the price of interchangeable drugs in the ATС - J05AF group does not differ statistically significantly between domestic and foreign manufacturers. Conclusion: In order to increase the level of import substitution of strategically important antiretroviral drugs, it is necessary, first of all, to solve the problem of providing Russian manufacturers with domestic pharmaceutical substances.

Treatment of human papillomavirus infection in HIV-infected patients

The first reports about HIV (human immunodeficiency virus) were appeared to the 1980s. By 2017 more than 37 million people were living with HIV. Human papilloma virus (HPV) is universally spread, with some estimates showing that about 1% of the sexually active population having genital warts. Human papilloma virus (HPV)-induced infection frequently accompanies the clinical course of HIV and can manifest itself in a full spectrum of clinical-pathologic forms ranging from common warts to malignant neoplasia. Due to the widespread use of antiretroviral therapy, the number of patients with a combined infection (HIV+HPV) is steadily increasing. Here we review current clinical treatment options for HPV manifestations. High-dose antiretroviral therapy does not impede HPV treatment, and can even improve its efficacy in some cases. The topical administration of imiquimod, an immune response modifier, is an effective conservative treatment in HIV-infected patients with HPV. The immunomodulation therapy of imiquimod can serve as an effective alternative of aggressive chemical and mechanical procedures. Maximum efficacy with the lowest replaces rates may be expected from combined use of mechanical ablation methods with a subsequent follow up treatment with imiqui-mod. The best therapeutic result is expected in HIV-positive patients who are received high-dose antiretroviral treatment. The advantages of Vartocid, the modified Russian equivalent of the generic imiquimod.

Leronlimab, a humanized monoclonal antibody to CCR5, blocks breast cancer cellular metastasis and enhances cell death induced by DNA damaging chemotherapy

BackgroundTriple-negative breast cancer (BCa) (TNBC) is a deadly form of human BCa with limited treatment options and poor prognosis. In our prior analysis of over 2200 breast cancer samples, the G protein-coupled receptor CCR5 was expressed in > 95% of TNBC samples. A humanized monoclonal antibody to CCR5 (leronlimab), used in the treatment of HIV-infected patients, has shown minimal side effects in large patient populations.MethodsA humanized monoclonal antibody to CCR5, leronlimab, was used for the first time in tissue culture and in mice to determine binding characteristics to human breast cancer cells, intracellular signaling, and impact on (i) metastasis prevention and (ii) impact on established metastasis.ResultsHerein, leronlimab was shown to bind CCR5 in multiple breast cancer cell lines. Binding of leronlimab to CCR5 reduced ligand-induced Ca+ 2 signaling, invasion of TNBC into Matrigel, and transwell migration. Leronlimab enhanced the BCa cell killing of the BCa chemotherapy reagent, doxorubicin. In xenografts conducted with Nu/Nu mice, leronlimab reduced lung metastasis of the TNBC cell line, MB-MDA-231, by > 98% at 6 weeks. Treatment with leronlimab reduced the metastatic tumor burden of established TNBC lung metastasis.ConclusionsThe safety profile of leronlimab, together with strong preclinical evidence to both prevent and reduce established breast cancer metastasis herein, suggests studies of clinical efficacy may be warranted.

Darunavir: A comprehensive profile.

Darunavir: (3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl [(2S,3R)-4-{[(4-aminophenyl)sulfonyl] (isobutyl)amino}-3-hydroxy-1-phenyl-2-butanyl]carbamate is a synthetic non-peptide protease inhibitor. On June 2006, it was first approved by the Food and Drug administration (FDA) for treatment of resistant type-1 of the human immunodeficiency virus (HIV). In July 2016, the FDA expanded the approval for use of darunavir in pregnant women with HIV infection. Darunavir prevents the replication of HIV virus by inhibiting the catalytic activity of the HIV-1 protease enzyme, and selectively inhibits the cleavage of HIV encoded Gag-Pol polyproteins in virus-infected cells, which prevents the formation of mature infectious virus particles. Darunavir is unique among currently available protease inhibitors because it maintains antiretroviral activity against a variety of multidrug-resistant HIV strains. This article discusses, by a critical extensive review of the literature, the description of darunavir in terms of its names, formulae, elemental composition, appearance, and use in the treatment of HIV-infected patients. The article also discusses the methods for preparation of darunavir, its physical-chemical properties, analytical methods for its determination, pharmacological properties, and dosing information.

Отличительные особенности результатов оперативного лечения внутрисуставных и внесуставных переломов у ВИЧ-инфицированных пациентов

The purpose — to evaluate the effectiveness of the developed algorithm for determining the tactics and methods of treating intraarticular fractures in HIV-infected patients. Material and methods. From 2016 to 2020, 56 HIV-infected patients with intra-articular fractures underwent surgical treatment. In the course of treatment, an algorithm developed in the clinic for determining the tactics and method of treating HIV-infected patients was used, which proved effective in treating extra-articular fractures. Results. The results were evaluated in the average expected time of the fracture consolidation of the selected location, as well as 6 and 12 months from the moment of surgery using the algorithm developed by us for determining the tactics and method of treating fractures in HIV-infected patients. Good results (according to the Luboschitz — Mattis scale) were noted in 16 (30,8%), satisfactory — in 27 (51,9%) and unsatisfactory — in 9 (17,3%) cases. For patients of this category, the most typical complications were the rapid progression of deforming arthrosis of the joints, the secondary displacement of bone fragments against the background of bone resorption, and the development of an inflammatory process of predominantly non-infectious etiology. Conclusion. The use of the developed algorithm for determining the tactics and method of treatment in HIV-infected patients with extra-articular fractures, taking into account the effect of HIV infection and antiretroviral therapy on the processes of bone remodeling and soft tissue regeneration, can significantly reduce the number of unsatisfactory treatment results. At the same time, the peculiarities of the effect of HIV infection on the state of cartilage, subchondral bone and synovial fluid determine the nature and risks of postoperative complications in HIV-infected patients. In the future, it is planned to correct the developed algorithm taking into account the data obtained and to carry out a comparative analysis of the treatment results.

Treatment Tactics and Complications After Surgical Treatment of HIV-Infected Patients With Extra-Articular Fractures of the Long Bones of Extremities

The aim of the study is the comparative analysis of the long-term results of treatment of extra-articular fractures of the long bones in HIV-infected and non-HIV-infected patients.Material and methods. In the presented study, a comparative analysis of the results of surgical treatment of 90 HIV-infected and 112 HIV-uninfected patients with extra-articular fractures of the long bones of the extremities aged from 23 to 54 years was performed.Results. HIV-infected patients are mainly characterized by non-infectious complications from the postoperative wound (formation of seromas, hematomas, dehiscence of the edges of wounds, delayed healing), aseptic loosening and migration of fixators, and delayed consolidation of fractures. The presence of statistically significant relationships between the factors characterizing the course of HIV infection (stage of the disease, the number of CD4 + lymphocytes, the ratio of CD4/CD8 + lymphocytes, viral load) and the risk of postoperative complications was revealed.Conclusion. Thus, the use of standard algorithms for determining the tactics and method of treatment of extra-articular fractures of the long bones of the extremities in HIV-infected patients leads to a significant number of unsatisfactory treatment results (up to 31.1%). For HIV-infected patients, the most typical complications are postoperative wounds, impaired fracture consolidation processes and aseptic loosening of metal fixators, which can lead to the development of infectious complications without proper attention. Expansion of research in this area with an increase in the number of observed contingents will make it possible to develop a scientifically based scale for predicting the development of possible postoperative complications in this category of patients.

Neurotoxicity of HIV-1 Tat is attributed to its penetrating property

We have recently engineered an exosomal Tat (Exo-Tat) which can activate latent HIV-1 in resting CD4+ T lymphocytes from antiretroviral treated HIV-1 infected patients. HIV-1 Tat protein can penetrate cell membrane freely and secrete into extracellular medium. Exo-Tat loses this penetrating property. HIV-1 Tat protein can damage the synaptic membranes contributing to the development of dementia in HIV-1 infected patients. To investigate whether the penetrating property attributes to synaptic damage in vivo, we have generated adeno-associated viruses AAV-Tat and AAV-Exo-Tat viruses. Vehicle control or AAV viruses (1 × 1012 GC/mouse in 200 μl PBS) were injected into Balb/cj mice via tail veins. The mRNA and protein expression levels in blood, brain, heart, intestine, kidney, liver, lung, muscle and spleen were determined on day 21. Intravenously injected AAV-Tat or AAV-Exo-Tat mainly infects liver and heart. Short-term expression of Tat or Exo-Tat doesn’t change the expression levels of neuronal cytoskeletal marker β3-tubulin and synaptic marker postsynaptic density 95 protein (PSD-95). Wild-type Tat, but not Exo-Tat, reduces the expression level of synaptic marker synaptophysin significantly in mice, indicating that penetrating property of HIV-1 Tat protein attributes to synaptic damage.