Oxidative stress, microparticles, and E-selectin do not depend on HIV suppression.

BACKGROUND: Oxidative stress and inflammation are considered predictors of diseases associated with aging. Markers of oxidative stress, inflammation, and endothelial activation were investigated in people with HIV on antiretroviral treatment to determine whether they had an immunosenescent phenotype that might predispose to the development of premature age-related diseases. PATIENTS AND METHODS: This study was conducted on 213 subjects with HIV. The control groups consisted of healthy HIV-negative adults. The level of oxidative stress was measured by assessing the production of malondialdehyde levels, which were detected by thiobarbituric acid reactive substance (TBARS) assay. The level of microparticles indicated the presence of inflammation and endothelial activation was measured by E-selectin levels. Significant differences were determined by appropriate statistical tests, depending on the distribution of variables. Relationships between continuous variables were quantified using Spearman's rank correlation coefficient. RESULTS: TBARS, and microparticle and E-selectin levels were significantly higher in untreated and treated subjects with HIV compared with HIV-negative controls (P<0.001). The levels of the investigated markers were not significantly different between untreated and treated patients and no significant correlation of these markers was found with CD4+ count, CD4+/CD8+ ratio, and the number of HIV-1 RNA copies. CONCLUSIONS: Elevated markers of oxidative stress, inflammatory and endothelial activation were independent of the virologic and immunologic status of people with HIV. These results support the hypothesis that residual viremia in cellular reservoirs of various tissues is a key factor related to the premature aging of the immune system and predisposition to the premature development of diseases associated with aging.

Implications of highly suppressive treatment HIV infection.

Treatment of HIV infection has modified the initially fatal infection into a typically chronic disease requiring lifelong treatment. However, there is no complete normalization of immune activation, signs of inflammation and prothrombotic state in treated patients. This condition is the result of many factors, but the main cause is thought to be the residual production of HIV-1 RNA and viral proteins by infected cells in cellular reservoirs. Persistence of immune activation/inflammation/prothrombotic state leads to the pathophysiology of "sterile inflammation" and so-called non-AIDS diseases, which manifest one to two decades earlier in those infected. Despite all the pitfalls and unwanted secondary manifestations of antiretroviral drugs, the treatment of HIV infection has managed to reverse the trajectory of a fatal pandemic and has made it possible to approach therapeutic modalities that were absolutely unimaginable just a few years ago. Solid organ transplantation is now a completely legitimate therapeutic method for patients living with HIV, and highly suppressive treatment even allows transplantation from an HIV-infected donor. The text below presents a brief overview of the basic pitfalls, but also of the successes, of the current highly suppressive treatment of HIV infection.

HIV-positive Ukrainian refugees in the Czech Republic.

OBJECTIVE: Over 480 000 Ukrainian refugees have arrived in the Czech Republic since the Russian invasion of Ukraine in 2022, including over 500 people with HIV. This study describes the demographics, characteristics, and management of Ukrainian refugees with HIV in the Czech Republic. DESIGN: Retrospective, observational, noninterventional study. METHODS: Ukrainian nationals registering at HIV centers in the Czech Republic with war refugee status were included. Data were collected from medical records between 1 March and 31 July 2022. The study was registered with the Czech State Institute for Drug Control, ID number 2301200000. RESULTS: Four hundred and eighty-two patients were included in the study. Most patients were female (69.5%; n  = 335/482) with well-controlled HIV. The median [interquartile range] CD4 + cell count was 597 [397] cells/µl of blood, and 79.3% ( n  = 361/455) of patients had HIV RNA <40 copies/ml. Coinfections of hepatitis C virus, hepatitis B virus, and/or tuberculosis were reported for 17.4% ( n  = 78/449), 9% ( n  = 40/446) and 1.3% ( n  = 6/446) of patients, respectively. In Ukraine, 85.7% ( n  = 384/448) of patients had been receiving an integrase strand transfer inhibitor-based regimen and most (69.7%; n  = 310/445) did not switch therapy upon arrival in the Czech Republic. CONCLUSION: Migration from Ukraine is changing the characteristics of HIV epidemiology in the Czech Republic. Ukrainian refugees with HIV have been provided with a high standard of medical care in the Czech Republic. Improved coordination between medical services within the Czech Republic and between countries in the European Union is necessary to optimize patient care.

Current hepatitis C therapy.

Hepatitis C virus (HCV) infection is still a major cause of chronic liver diseases, with approximately 71 million chronically infected persons worldwide. People who inject drugs currently or in the past (PWID), mostly intravenously, are the main risk group among HCV chronically infected persons. The efficacy of therapy with direct acting antivirals (DAA) is almost 100 %. Currently, the main mission is to diagnose HCV infection in the most possible number of infected persons; it is in collision with poor adherence of PWID in particular.

Circulating microparticles in patients with chronic hepatitis C and changes during direct-acting antiviral therapy.

BACKGROUND: Microparticles (MPs) are heterogeneous vesicles derived from membranes of different cells. Between 70 to 90% of MPs detected in blood originate from platelets. The release of MPs is associated with proinflammatory and procoagulant states. Elevated levels of MPs have been found in different diseases. We investigated MPs levels in patients with chronic hepatitis C (CHC) and changes in level during treatment using direct-acting antivirotics (DAA). PATIENTS AND METHODS: Thirty-six patients with CHC and forty healthy volunteers were included in the study. Concentrations of MPs were determined indirectly by measuring their procoagulant activity in plasma at baseline, end of therapy (EOT), and 12 weeks after EOT when the sustained virological response was assessed (SVR12). RESULTS: All patients achieved SVR12, which was associated with rapid improvement of markers of liver damage and function as well as liver stiffness (P=0.002). MPs levels were significantly higher in CHC patients than in healthy volunteers (P<0.001). No statistically significant decrease was found observed between baseline and SVR12 (P=0,330). Analysis of subpopulations with minimal fibrosis F0-1 (P=0.647), advanced fibrosis F2-4 (P=0.370), women(P=0.847), men (P=0.164) and genotype 1 (P=0.077) showed no significant changes during the follow-up period. CONCLUSIONS: MPs levels are higher in CHC patients and remain elevated shortly after achieving SVR. Higher concentrations of MPs in plasma are probably caused by a chronic uncontrolled exaggerated inflammatory response caused by CHC. Longer observation would probably confirm the significance of MPs levels decrease because normalization of liver function, inflammation, and structure after SVR requires more than 12 weeks.

[Hepatitis D screening is important in the Czech Republic as well].

Only patients infected with hepatitis B virus (HBV) can contract hepatitis D virus (HDV) infection, either simultaneously (co-infection) or as a superinfection in those already infected with HBV. The routes of HDV transmission are contaminated needles or transfusion; sexual and vertical transmissions are relatively rare. Chronic hepatitis D is the most serious form of chronic viral hepatitis due to more rapid progression to decompensated cirrhosis and hepatocellular carcinoma (HCC). Liver cirrhosis may develop within five years and HCC within 10 years of dual infection. In the vast majority of cases, HDV replication suppresses HBV replication. Therefore, most patients are positive for HDV RNA in plasma while showing no or low levels of HBV DNA. At present, there is no routine screening for HDV in persons with chronic HBV infection in the Czech Republic. One of the reasons the absence of approved treatment op-tions, with the only possibility being administration of pegylated interferon alpha for 48 weeks or even longer. This approach does not provide long-term efficacy in most cases. Therapy with bulevirtide seems to be promising according to available data.

[Dual or triple combination antiretrovirals?]

Since the beginning of the antiretroviral therapy (ART) era, its extraordinary effect in terms of morbidity and mortality has been linked to a three-drug combination HIV treatment strategy, which has been perceived as a constant paradigm for many years. However, epidemiological studies over the past decade have clearly shown that ART does not result in complete normalization of all biomarkers, and some degree of systemic immune activation and inflammation, including endothelial dysfunction, persist. It is generally accepted that these pathophysiological processes are the cause of non-AIDS diseases, which are clinically manifested in people living with HIV on average 10 years earlier than in the general HIV-negative population. HIV treatment is not eradicative but only inhibitive and requires regular daily medication. This increases the risk of the cumulative impact of side effects and drug toxicity. In addition, it is expected that there will be a significant increase in the number of patients with various other non-AIDS comorbidities that will require multiple medication in the coming years. In particular, the higher genetic barrier of the new generation of drugs and an improved safety profile have raised the question of the effectiveness of two-drug combination regimens with the fundamental goal of reducing the burden on the human body by different drugs while maintaining high efficacy fully comparable to the current three-drug combination strategy. However, the question of whether dual combination regimens can sufficiently suppress the persistence of chronic inflammation and immune activation remains unanswered. To answer such a question, robust data from large prospective randomized studies are needed, which are still lacking. This review discusses the principle of systemic immune activation, its regenerative potential in ART, the expected causes leading to systemic immune activation, intervention options to influence it, as well as the limitations of studies to date.

[Cost-effectiveness analysis for HIV pre-exposure prophylaxis in a high-risk population in the Czech Republic].

OBJECTIVES: To assess the cost-effectiveness of pharmacological pre-exposure prophylaxis (PrEP) using a combination of emtricitabine and tenofovir disoproxil fumarate (FTC/TDF) with respect to HIV transmission in high-risk patients in the Czech Republic. MATERIAL AND METHODS: A pharmacoeconomic model was constructed to compare costs and outcomes in a cohort with and without PrEP. Initially, a decision tree is used to evaluate short-term benefits of PrEP (proportion of HIV-infected individuals), followed by Markov cycles to simulate the course of the disease based on CD4 lymphocyte counts. The efficacy of PrEP, probability of transition between HIV infection stages, costs per category and quality of life data were derived from the literature. The results are presented as an incremental cost effectiveness ratio of incremental costs and incremental quality adjusted life-years (ICER/QALY) in a lifetime horizon with a 3% annual discount rate of costs and benefits. RESULTS: The FTC/TDF prophylaxis is dominant, that is, it generates lower costs and higher benefits (expressed as QALYs) in comparison with the control group without prophylaxis. A sensitivity analysis modelled all relevant parameters and all scenarios confirmed the PrEP dominance. CONCLUSIONS: A cost-effectiveness analysis in the Czech Republic setting confirmed that pharmacological PrPE intervention is cost-effective, or cost-saving, in a high-risk population of men having sex with men, using a lifetime horizon.

[Guidelines for treating HIV-infected adults and post-exposure prophylaxis for HIV infection].

Antiretroviral therapy represents an essential element in the approach to treatment and prevention of human immunodeficiency virus (HIV). It has changed the fatal disease to a manageable chronic condition and is the most effective prevention of its human-to-human transmission. Knowledge regarding biological characteristics of the virus, its behavior in a human host and our understanding of these phenomena have been extended by clinical experience, new clinical data and recent scientific progress. The development of new drugs becomes a modifier for the existing therapeutic strategy and preference. Certain points are more specific than in the previous guidelines. Definitions of certain clinical and laboratory conditions have been specified more accurately. The indications of specific antiretroviral agents and pitfalls of their use in lifelong antiretroviral treatment are also described more in detail. The document is a result of a general consensus among infectious disease specialists working with HIV patients in the Czech Republic. It should serve as a basic instrument for clinicians recommending treatment of HIV infection as well as a foundation for the society when dealing with both state authorities and health care payers.

[HIV infection - a new disease of internal medicine]. / Infekce HIV jako nové onemocnení vnitrního lékarství.

Modern antiretroviral treatment belongs to the greatest success of current medicine. HIV infection has gone from a death sentence to a manageable chronic disease which develops several decades. Thanks to treatment advances, people with HIV can and do live long and full lives. In the last two decades, the incidence AIDS defining illnesses have been dramatically reduced especially opportunistic infections and malignancies, whereas the role of non-infection comorbidities has risen than age-matched HIV uninfected adults. These comorbidities include cardiovascular diseases, venous and arterial thrombosis, metabolic disorders, chronic liver and renal diseases, nervous system disorders, osteoporosis and some cancers. This relatively large group of diseases is known as non-AIDS defining or indicating diseases and these diseases are associated in HIV uninfected general population with older age and ageing Most HIV positive individuals on antiretrovirals present an abnormal level of immune activation, inflammation and hypercoagulable condition. These hallmarks are typically seen in older HIV uninfected general population and are associated with aging and the immunosenescent phenotype. The explanation for this phenomenon is unclear. There are multiple factors, which may apply pathophysiologically, including the residual immune dysregulation syndrome and antiretrovirals alone. It is clear that changes in the nature of chronic HIV infection put it in internal medicine. Cardiology, internal medicine, geriatric and oncology syndromes are dominating manifestations in HIV positive patients on antiretrovirals. Care management for HIV infected individuals will need to draw on a wide range of medical disciplines in diagnosis and treatment. Clarification of these phenomena would be beneficial for the treatment of these non-infectious diseases in HIV positive and as well in HIV negative general population.Key words: antiretroviral therapy - HIV infection - immune dysregulation - immunosenescence - non-AIDS disease.

[Tenofovir alafenamide fumarate - a new generation of tenofovir].

Antiretroviral therapy as a life-long treatment has to meet the criteria of maximum efficiency while maintaining the highest possible level of safety and tolerance. Tenofovir disoproxil fumarate (TDF) is an antiretroviral drug with an excellent effect of virological suppression. However, some patients can over time develop clinically significant nephrotoxicity or bone loss. Tenofovir alafenamide fumarate (TAF) is a novel prodrug of tenofovir (TFV) that is more stable in human plasma and more efficiently penetrates into target cells than TFV. Tenofovir converted from TAF reaches plasma concentration which is 90% lower than that of TFV converted from TDF. Conversely, the active metabolite converted from TAF reaches a higher intracellular level in target cells than TFV from TDF. This allows a substantial reduction of its oral dose, decreasing the risk for renal and bone toxicity. It is even possible to reduce the dose of TAF in case it is administered concurrently with cobicistat further improving its absorption and optimizing its pharmacokinetic profile. Pharmacokinetic properties are another factor substantially influencing its safety profile. TAF is not a substrate for renal organic anion transporters and thus shows no cytotoxicity related to their expression. Based on clinical trials, a fixed-dose combination tablet (single-tablet regimen) containing elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide fumarate was approved by the FDA in November 2015. This regimen showed higher efficacy, better safety profile and tolerance than TDF-based regiments. Recently, it has been approved in European Union countries.

[Guidelines for caring for HIV-infected adults and post-exposure prophylaxis of HIV infection].

Presented are general principles of care for HIV-infected persons following their admission to an AIDS care center, initiation of antiretroviral therapy and follow-up. Scientific research, drug development and new clinical data in recent years have led to a change in certain therapeutic perspectives and preferences for the treatment of HIV infection. Certain conditions are better specified, which affect the choice of antiretroviral regimens. Procedures and criteria for monitoring the effect of treatment and indication of post-exposure prophylaxis are specified. The development of this document was based on the latest updates of the most prominent international and European recommendations. It also reflects some of the new scientific information published in recent months. However, general recommendations cannot fully cover all the possible alternatives. They only state basic principles based on current clinical studies, clinical observation and practice. The present document should be the basic source of information for physicians involved in the treatment of patients with HIV infection and should provide a quick reference when selecting treatment regimens in terms of modern pharmacotherapy as well as information on the pitfalls of this treatment. Finally, it should be a support for negotiations between the professional society, state authorities and health care payers.This updated version of the guidelines follows the 2012 edition; once again, they are supplemented by a modified tabular overview.

[RILPIVIRINE -- a novel HIV-1 non-nucleoside reverse transcriptase inhibitor]. / RILPIVIRIN -- nový nenukleosidový inhibitor reverzní transkriptázy HIV-1.

The article summarizes the basic facts about the pharmacokinetic profile, metabolism and drug interactions of rilpivirine (RPV). This is the latest orally administered second-generation non-nucleoside reverse transcriptase inhibitor (NNRTI) for antiretroviral-naive patients with HIV-1 infection. Conformational flexibility and adaptability are the factors that dominantly determine the high resistance barrier of RPV and are the unique features of diarylpyrimidine inhibitors (DAPY inhibitors - 2nd generation NNRTIs). Multicentre studies ECHO and THRIVE are also reviewed. Current guidelines for the treatment of HIV/AIDS are mentioned as well as the role of RPV in current therapeutic regimens.

Acute toxoplasmosis-etiological factor for development of Hodgkin's lymphoma?

The case of an HIV-positive man treated for acute toxoplasmosis with no traces of malignancy is reported. A second lymph node extirpation was performed after 5 months, which identified the presence of Hodgkin and Reed-Sternberg (HRS) cells. This case suggests that toxoplasmosis may cause changes in the regulation of surrounding cells and induce neoplastic proliferation.

Prevalence of human leukocyte antigen HLA-B*57:01 in HIV-infected subjects in the Czech Republic.

The HLA-B*57:01 allele is associated with a hypersensitivity reaction to abacavir, and its prevalence varies in different populations. The aim of the study was to investigate HLA-B*57:01 prevalence in the Czech HIV-infected population. HLA-B*57:01 prevalence in our cohort was 5.33%, which is similar to the situation in other Central European countries.

[Disseminated infection with Mycobacterium avium in a patient with newly diagnosed HIV infection]. / Diseminovana infekce Mycobacterium avium u pacienta s nove zjistenou HIV infekci.

In the Czech Republic, mycobacteriosis is relatively rare. The low incidence probably reflects high BCG coverage rates in the Czech population. Globally, the importance of BCG vaccine has been increasing, as a result of acquired immunodeficiencies, particularly HIV infection. The presented case report describes the course of disseminated mycobacteriosis in a Vietnamese asylum seeker with newly diagnosed advanced HIV infection. In HIV patients, disseminated mycobacteriosis, most frequently caused by members of Mycobacterium avium complex (MAC), is mostly manifested in the last stage, AIDS, with extremely severe immunodeficiency, or in immune reconstitution inflammatory syndrome (IRIS), shortly after initiation of antiretroviral therapy. From the beginning, the patient's condition was complicated by multiple simultaneous severe opportunistic infections which, together with gradually progressing atypical mycobacteriosis, resulted in overall exhaustion of the organism. The adverse prognosis of these infections is significantly influenced by prolonged diagnosis based on culture detection of slow-growing mycobacteria. In the above patient, the lethal course was contributed to by resistance to commonly used antitubercular drugs which was only detected post mortem due to time-consuming susceptibility tests.

[Kaposi's sarcoma]. / Kaposiho sarkom.

Kaposi's sarcoma (KS) is an unusual form of tumor which in the era of HIV/AIDS pandemic is increasingly observed outside the original endemic areas. It was shown that the development of KS is in directly related to infection with human herpes virus 8 (HHV-8). The pathophysiology of KS is complex and is influenced by HIV co-infection and by global cytokine interactions. Skin, gastrointestinal tract and respiratory organs are typically involved. A good therapeutic effect of combined antiretroviral therapy (cART) was documented. We provode a review of the current knowledge of the pathophysiology of and therapeutic options for KS and one clinical case.

[Guidelines for antiretroviral therapy of human immunodeficiency virus (HIV)-infected subjects in the Czech Republic]. / Komplexní postup antiretrovirové lécby osob infikovaných virem lidské imunodeficience (HIV) v Ceské republice.

HIV infection remains an incurable disease because of the impossibility to eradicate the HIV from the organism. However, the combination antiretroviral therapy (cART) is able to efficiently limit HIV replication and slow down progression of immunodeficiency and thus prolong and improve the quality of HIV+ patients? lives. In HIV(+) pregnant women, the antiretroviral therapy substantially reduces the risk of vertical transmission of the infection. According to present knowledge, the cART is indicated mainly in symptomatic patients with stage B or C diseases and for vertical transmission and postexposure prophylaxis; less clear is the indication of cART for treating acute HIV infection and in asymptomatic patients. Various guidelines for the use of antiretroviral agents issued worldwide, e.g. in the USA, Europe or by the WHO, are not completely identical. The authors present a draft of recommendations for the use of antiretroviral agents in the Czech Republic based on the above-mentioned guidelines as well as on their own experience with taking care of HIV/AIDS patients.

[Metabolic syndrome and HIV/AIDS disorder]. / Metabolický syndrom u onemocnìní HIV/AIDS.

Up-to-date therapy has in recent years substantially modified the clinical course of HIV infections and AIDS. The progress of the disorder has changed-today it is a chronic disease of many years. Already in 1997 and 1998 it transpired that long-term HAART, highly active antiretroviral therapy, produced adverse metabolic changes, which significantly affect the subsequent progress of the disease. The mechanism responsible for these metabolic changes has not, as yet, been fully clarified-in all probability its etiology is multifactorial. Even prior to the introduction of HAART, some metabolic changes were observed in HIV-infected subjects. These changes are, however, not specific for the pathogen concerned, they are generally seen in acute inflammatory reactions. Since the introduction of HAART in 1996 the range of metabolic changes has expanded. Gradually we detect more and more anthropometric, metabolic and coagulation changes, closely resembling changes seen in the metabolic syndrome (SIR, syndrome of insulin resistance), well known from cardiology and internal medicine-dyslipoproteinaemia, insulin resistance, abdominal obesity. A combination of these disorders is clinically significant due to their role in the development of atherosclerosis and their by no means negligible involvement in the onset of ischaemic heart disease. In view of the much lower mean age of HIV-positive subjects the earlier mentioned complications should be expected in much lower age categories than with HIV-negative individuals. The paper discusses the possible pathogenesis and potential mechanisms of metabolic complications related to HAART, its impact on the cardiovascular risk and the possibilities of hypolipidaemic therapy in HIV-positive patients.

[Haemopoiesis defects in HIV/AIDS-anaemia.].

Under physiological conditions haemopoiesis is continuous and maintains a stable number of blood elements. A defect at any stage presents as anaemia, neutropenia, thrombocytopenia or their combinations. The cause of haematological abnormalities with an HIV infection is multifactorial. HIV/AIDS patients may present identical haematological disorders as patients free of an HIV infection. Additionally, HIV-positive subjects tend to present disorders specific of an HIV infection. Anaemia may also be the first manifestation of an as yet undetected HIV infection. Moreover, many drugs used in the treatment of HIV/AIDS significantly affect haemopoiesis. Whatever the cause of anaemia, it is essential to initiate simultaneously with its treatment an appropriate highly active antiretroviral therapy. An antiretroviral therapy along the lines of state-of-the-art pharmacotherapy of HIV/AIDS significantly improves the efficacy of the actual haematological treatment. Key words: HIV infection-haemopoiesis-anaemia-antiretroviral therapy.